At the age of 15, he assumed the rule over the Netherlands. His scope of activities soon widened. After the death of his maternal grandfather, Ferdinand II, in 1516, Charles was proclaimed sovereign of Spain, together with his mother (who, however, suffered from a nervous illness and never reigned). In September 1517 he landed in Spain, a country with whose customs he was unfamiliar and whose language he was as yet barely able to speak. There he instituted, under Burgundian influence, a government that was little better than foreign rule. When his election as king of Germany in 1519 (his paternal grandfather, the Habsburg emperor Maximilian I, having died) recalled him to Germany, Charles left behind him, after some two and one-half years in Spain, a dissatisfied and restless people. Adrian, whom he had installed as regent, was not strong enough to suppress the revolt of the Castilian cities (comuneros) that broke out at this point. Making the most of their candidate's German parentage and buying up German electoral votes (mostly with money supplied by the powerful Fugger (Fugger Family) banking family), Charles's adherents had meanwhile pushed through his election as emperor over his powerful rival, Francis I of France.

In October 1520 Charles was accordingly crowned king of Germany in Aachen, assuming at the same time the title of Roman emperor-elect. In the spring of 1521 the imperial Diet (Diet of Worms), before which Martin Luther (Luther, Martin) had to defend his theses, assembled at Worms. The reformer's appearance represented a first challenge to Charles, who had his own confession of faith, beginning with a sweeping invocation of his Catholic ancestors, read out to the Diet. Rejecting Luther's doctrines in the Edict of Worms, Charles declared war on Protestantism.

After defeating Duca Massimiliano Sforza at Marignano in 1515, the reigning Valois, Francis I, compelled him, in the Treaty of Noyon, to renounce his claim to the Duchy of Milan. The vanquished Sforza turned for help to Pope Leo X and Charles V, with whom he concluded a treaty in 1521. Despite the outbreak of war with France, Charles hurried back to Spain, where his followers had meanwhile gained the upper hand over the comuneros. Even though he granted an amnesty, the young monarch proved to be an intransigent ruler, bloodily suppressing the revolt and signing 270 death warrants. These actions were nevertheless followed by a rapid and complete rapprochement between the pacified people and their sovereign; in fact, it was during this second and protracted sojourn in Spain (1522–29) that Charles became a Spaniard, with Castilian grandees replacing the Burgundians. There soon developed an emotionally tinged understanding between Charles and his Spanish subjects that was to be steadily deepened during his long rule. Henceforth, it was primarily the material resources of his Spanish domains that sustained his far-flung policies and his Spanish troops who acquitted themselves most bravely and successfully in his wars.

In 1522 his teacher Adrian of Utrecht became pope, as Adrian VI. His efforts to reconcile Francis I and the Emperor failed, and three years later Charles's army defeated Francis I at Pavia (Pavia, Battle of), taking prisoner the King himself. The victory assured Spanish supremacy in Italy. Held in the alcazar of Madrid (Madrid, Treaty of), the royal captive feigned agreement with the conditions imposed by Charles, even taking the Emperor's oldest sister, Eleanor, the dowager queen of Portugal, for his wife and handing over his sons as hostages. But, as soon as he had regained his freedom, Francis rejected the terms of the Treaty of Madrid of January 1526.

With the accession of Süleyman the Magnificent (Süleyman I) to the sultanate in 1520, Turkish (Ottoman Empire) pressure on Europe increased once more. The Sultan threatened not only Hungary but also those hereditary provinces of the Habsburgs that, by Charles's agreement in 1522 with his brother Ferdinand (Ferdinand I), henceforth belonged to the younger branch of the Habsburgs. When Louis II of Hungary and Bohemia was defeated and killed by the Turks in the Battle of Mohács in August 1526, Ferdinand assumed this throne both as the childless former monarch's brother-in-law and by virtue of the treaty of succession concluded in 1491 between his own grandfather and Louis' father, Vladislov II. After this, the Turkish danger became the Habsburgs' foremost concern on land, as it had been on the seas ever since Charles's accession to the throne of Spain. Although Charles realized that his first duty as emperor of Christendom lay in warding off this peril, he found himself so enmeshed in the affairs of western Europe that he had little time, energy, and money left for this task. In 1526 Charles married Isabella, the daughter of King Manuel I of Portugal.

In early 1527, instead of fighting the infidel, Charles's Spanish troops and his German mercenaries marched against the Pope, his enemy since the establishment of the League of Cognac. Mutinous and with their pay in arrears, they entered the defenseless city of Rome and looted it during the infamous Sack of Rome (May 1527).

The Pope, having surrendered to the mutinous troops, was now ready for any compromise. The newly started war between the Emperor and France also came to a close when the mother of Francis I approached Margaret of Austria, the Emperor's aunt, through whose mediation the “ladies' peace” of Cambrai (Cambrai, Treaty of) was concluded in August 1529. The status quo was preserved: Charles renounced his claim to Burgundy, Francis his claims to Milan and Naples. The Pope, having made peace with Charles, met him in Bologna; there he crowned him emperor in February 1530. It was to be the last time that a Holy Roman emperor was crowned by a pope.

In 1530, Charles, attempting to bring about a reformation within the Catholic Church through the convocation of a universal council, also tried to find a modus vivendi with the Protestants (Protestantism). The Catholics, however, replied to the Confession of Augsburg (Augsburg Confession), the basic confessional statement of the Lutheran Church, with the Confutation, which met with Charles's approval. The final decree issued by the Diet accordingly confirmed, in somewhat expanded form, the resolutions embodied in the Edict of Worms of 1521. This, in turn, caused the Protestant princes to close ranks in the following year in the Schmalkaldic League. Faced with renewed Turkish onslaughts, the Emperor granted some concessions in return for armed support against the enemy. In 1532 a large army under Charles's personal command faced Süleyman's forces before the city of Vienna, but the order to give decisive battle was withheld. Instead, the Emperor returned to Spain in 1533, leaving his brother Ferdinand behind as his deputy.

By taking up his grandfather Ferdinand of Aragon's project of conquering North Africa, Charles endeavoured to undertake by sea what he had omitted to do on land. The attempt to repulse the corsair (Barbary pirate) (and Turkish general) Barbarossa (Khayr ad-Dīn) was nonetheless no more than a marginal operation, since Charles's capture of Ḥalq al-Wādī and Tunis (1535) did nothing to diminish the strength of Süleyman's position.

From Africa, the Emperor sailed to Naples, entering Rome in 1536 to deliver his famous political address before Pope Paul III and the Sacred College of Cardinals, in which he challenged the King of France (who had meanwhile invaded Savoy and taken Turin) to personal combat. When Francis declined, Charles invaded Provence in an operation that soon faltered. Through the Pope's intercession, peace was concluded in May 1538.

Intent on suppressing the open revolt that had broken out in Ghent, his native city, the Emperor himself went to the Netherlands. The country's regent, Charles's sister, Mary of Hungary, had proved incapable of settling the conflict between herself and the city, which jealously guarded its prerogatives. On his arrival in February 1540, Charles revoked Ghent's privileges, had 13 leading rebels executed, and gave orders to build a fortified castle. Once again his actions, as severe as those he had taken against the comuneros in 1522, were crowned by success. Toward the German Protestants, on the other hand, he showed himself conciliatory; in 1541 the Diet of Regensburg granted them major concessions, even if these were later rejected by both the Pope and Luther. Although Ferdinand, having lost his Hungarian capital in August 1541, pleaded for a land campaign against Süleyman, Charles again decided on a naval venture, which failed dismally after an unsuccessful attack on Algiers.

When Charles enfeoffed his son Philip (Philip II) with Milan, the King of France, enraged because he had hoped to regain indirect control of Milan himself, rearmed and declared war in August 1542. Fighting broke out the following year, even though the Pope had finally convoked, in Trent, the council for which the Emperor had been pressing. Once again Charles's precarious financial situation partially accounted for the failure of his plans. His finances were in a perpetually unsettled state. The “Indian” possessions in America (Latin America, history of) were, of course, in an uninterrupted state of expansion throughout his entire reign, marked by, among other ventures, the conquest of Mexico and the conquest of Peru. The gold from the Indies did not add up to any sizable sum at the time. Only in 1550 did 17 Spanish ships provide the Emperor with 3,000,000 ducats and others with a like sum in the earliest significant monetary transfusion from the New World. The silver mines of Potosí were not exploited systematically until the 1550s, so that their revenue arrived too late for Charles. In 1516 the floating debt amounted to 20,000 livres; by 1556 it had risen to 7,000,000. In 1556, the exchequer owed 6,761,272 ducats. Thus, the campaign of 1543–44, inadequately financed, bogged down. It was to no avail that the French and imperial armies faced one another in the field in November 1543 and again in August 1544. As in 1532, when Charles had faced the Turks before Vienna, neither side cared to open hostilities, with the result that the peace of Crepy (September 1544) again more or less confirmed the status quo.

The Council of Trent did not open until December 1545, but Paul III had earlier offered Charles men and money against the heretics. When the Protestant princes failed to put in an appearance at the imperial Diet of Regensburg in 1546, the religious and political situation turned critical once again. Charles prepared for war. In a battle that decided the whole campaign and placed his archenemies at his mercy, the Emperor (who had been attacked by the German princes the previous September) defeated the Protestants at Mühlberg in April 1547. Ill much of the time, he spent the following year at Augsburg, where he succeeded in detaching the Netherlands from the imperial Diet's jurisdiction while yet assuring their continued protection by the empire. Also in Augsburg, he drew up his “political testament” for Philip and reorganized the Spanish court. The Diet of Augsburg furthermore saw the publication of the “Interim,” a formula conciliatory to the Protestants but retaining the Roman Catholic ritual in general. Although Charles believed that he had granted far-reaching concessions to the people and the Protestant authorities in this document, his main concern was to make the Protestants return to the Catholic Church.

North Germany was now on the brink of revolt. The new king of France, Henry II, was eagerly awaiting an opportunity to renew the old rivalry between the houses of Valois and Burgundy, while the German princes believed that the moment was at hand to repay Charles for Mühlberg. After a secret treaty was signed in October 1551 between Henry II, Albert II Alcibiades, margrave of Brandenburg, and Maurice, elector of Saxony, Maurice in January 1552 ceded to France the cities of Metz, Toul, and Verdun, thus handing over imperial lands. When Maurice tried to capture the Emperor himself, the latter barely managed to escape. He soon gathered reinforcements, but the changed political situation compelled him to ratify an agreement made between his brother Ferdinand and the rebels, according to which the new Protestant religion was to be granted equal rights with Roman Catholicism. Charles's attempt to retake Metz that fall ended in a complete fiasco, with Burgundy capitulating to Valois and the Emperor defeated in his struggle for hegemony in western Europe.

In order to save what he could of this hegemony, Charles, already severely racked by gout, tried new paths by preparing the ground for his widowed son's marriage with Mary I of England. It looked for a while as if his great hopes were about to be fulfilled, the joining of north and south and the realization of the dream of a universal empire. But, even though Philip married Mary in July 1554, the English Parliament emphatically refused to crown him. Since Mary remained childless, Charles's hopes came to naught. After an abortive last campaign against France, he prepared for his abdication, renouncing, in 1555 and 1556, his claims to the Netherlands and Spain in favour of Philip and those to the imperial crown in Ferdinand's favour. Disembarking in Spain at the end of September 1556, he moved to the monastery of Yuste, which he had long ago selected as his final refuge, in early February 1557. There he laid the groundwork for the eventual bequest of Portugal to the Habsburgs after King Sebastian's death with the help of his sister Catherine, grandmother of Sebastian and regent of Portugal. He aided his son in procuring funds in Spain for the continuation of the war against France, and he helped his daughter Joan, regent of Spain during Philip's absence in the Netherlands, in persecuting Spanish heretics.

Not only the task but the man to whom it was given had a dual nature. By background and training, Charles was a medieval ruler whose outlook on life was stamped throughout by a deeply experienced Catholic faith and by the knightly ideals of the late chivalric age. Yet his sober, rational, and pragmatic thinking again mark him as a man of his age. Although Charles's moral uprightness and sense of personal honour make it impossible to regard him as a truly Machiavellian statesman, his unswerving resolve and his refusal to give up any part whatsoever of his patrimony are evidence of a strong and unconditional will to power. More than that, it is precisely this individual claim to power that forms the core of his personality and explains his aims and actions.

Charles's abdication has been variously interpreted. While many saw in it an unsuccessful man's escape from the world, his contemporaries thought differently. Charles himself had been considering the idea even in his prime. In 1532 his secretary, Alfonso de Valdés (Valdés, Alfonso de), suggested to him the thought that a ruler who was incapable of preserving the peace and, indeed, who had to consider himself an obstacle to its establishment was obliged to retire from affairs of state. Once the abdication had become a fact, St. Ignatius of Loyola (Loyola, Saint Ignatius of) had this to say:

In this last, metaphysically tinged period of his life, Charles's freedom consisted in his conscious and conscientious preparation for the buen morir, for a lucid death.

Having purchased the Dauphiné (on France's southeastern frontier) in 1349, Charles bore the title of dauphin until his coronation. After his father, King John II the Good, was captured by the English at Poitiers in 1356, Charles, in order to raise his father's ransom money, had to convene a hostile States General, which, led by Étienne Marcel (Marcel, Étienne), provost of the Paris merchants, forced him to issue an ordinance of reform on March 3, 1357. To frighten Charles further, Marcel had two of the king's councillors assassinated in the palace in Charles's presence in February 1358. Charles, in order to raise an army, left Paris to convoke an assembly of his supporters. On July 31, 1358, Marcel was assassinated.

When Charles reentered Paris on Aug. 2, 1358, his military situation remained precarious because he still had to fight both the English and his archenemy, the King of Navarre. The treaties of Brétigny and of Calais (May and October 1360) granted to Edward III of England most of southwestern France and 3,000,000 gold crowns for John's ransom.

Charles ascended the French throne on April 8, 1364, on John's death. He then challenged the King of Navarre over the succession of Burgundy. Bertrand du Guesclin, Charles's brilliant military leader, defeated the Navarrese at Cocherel in May 1364 but was defeated at Auray the following September by the English-backed side in a renewal of an old dispute over the Breton succession.

When war broke out again with England in 1369 over France's failure to abide by its treaty obligations, Charles followed du Guesclin's military advice, winning for the French so many victories that, by 1375, the settlement of 1360 was virtually nullified. In 1378, after learning of plots of the King of Navarre, Charles dispossessed him of all his French lands except Cherbourg. That December Charles made, unsuccessfully, his last attempt to deprive Duke John IV of Brittany. Charles's last political acts were primarily concerned with the rivalry between the two newly elected popes; his decision to support Clement VII made him chiefly responsible for the great schism of the papacy.

In his court Charles, an intellectual and religious man, surrounded himself with luxury and men of educated tastes. Besides reorganizing the army, creating a new navy, instituting tax changes, and bringing Flanders, Spain, and Portugal into French alliances, he was also concerned with redecorating the Louvre to house a magnificent library and with finishing the castle of Vincennes.