Enea Silvio Piccolomini was born in the village of Corsignano, near Siena, Italy, into a noble family in very reduced circumstances. He acquired his humanistic education by assiduous work under unfavourable conditions. To earn a living he became secretary to Cardinal Domenico Capranica and went with him to the Council of Basel (Basel, Council of), a meeting of bishops concerned with church reform (1431–37), which was already at loggerheads with Pope Eugenius IV. With Cardinal Niccolò Albergati he visited many European countries on a diplomatic mission. On returning to Basel in 1436, he became an official of the council, which gave him opportunities to show his great skill as an orator. He became secretary to the antipope Felix V, elected on Nov. 5, 1439, by the remnant of bishops at Basel, who refused to obey Pope Eugenius' order to transfer the council to Ferrara and Florence.

As representative of the Basel remnant at the Diet (imperial assembly) of Frankfurt, he attracted the attention of Frederick III of Austria, who invited him to Vienna (1442) and made him imperial poet laureate and his private secretary. Thereupon, he broke his connection with the antipope in 1445 and was absolved of the ban of excommunication that he had been under. A serious illness is said to have led him to amend his dissolute life (he was the father of several illegitimate children). In Frederick's name he proposed to end the rivalry between the papal council at Florence and the rebellious council at Basel by summoning a third council but could persuade neither Eugenius nor the bishops at Basel. Hitherto a layman, Enea received sacred orders in 1446. He next managed to calm the storm raised by Eugenius' deposition of two of the German archbishop electors and was chiefly responsible for reconciling the German princes with the Pope and for Frederick's withdrawal of support for the council at Basel.

Made bishop of Trieste by the new pope, Nicholas V, in 1447, he continued his successful mediation between the German states and the Holy See, explaining in a “letter of retractation” his change of role from supporting Basel to being advocate of the papacy. He was transferred in 1449 to the see of Siena, where he was still able to be of service to King Frederick by negotiating his marriage with a Portuguese princess and arranging his coronation as Holy Roman emperor in Rome by Nicholas V (1452). Nicholas' successor, Calixtus III (1455–58), made Enea cardinal-priest of Santa Sabina as a reward for negotiating peace with Alfonso V, king of Aragon and Naples, and persuading him to cooperate in the crusade against the Turks that Calixtus was energetically promoting.

On Calixtus' death Enea Silvio was elected pope as Pius II (Aug. 19, 1458). As pope he had one main purpose: to organize a grand crusade (Crusades) to drive back the Turks, who, having captured Constantinople in 1453, were threatening to overrun the rest of Europe. He summoned the Christian princes to a congress in Mantua to study and meet the danger. When he arrived on the appointed day, June 1, 1459, he was alone. Very gradually some came but only to squabble for advantages to themselves.

The patient diplomacy of the Pope achieved little. A condition for success was to restore peace to the West. In Italy, Pius slowly regained control of the Papal States. His negotiations with France for the repeal of the Pragmatic Sanction of Bourges (of 1438, which made France largely independent of the papacy in ecclesiastical jurisdiction) failed with King Charles VII but succeeded with his son Louis XI (1461). The Greek cardinal Bessarion was sent to Germany (1460) to promote the crusade, but local feuds and wars blocked his efforts. He was equally unsuccessful in Vienna and returned to Rome in the following year but had some success later in Venice. Wars in the Tyrol and discord in Bohemia increased the general unrest. A lull in some hostilities and promises of support from the emperor Frederick and Philip the Good, duke of Burgundy, encouraged the intrepid but sick pope to proclaim in October 1463 a crusade, which he himself would lead. Pius left Rome on June 18, 1464, for the rendezvous of the armies in Ancona, an Adriatic seaport on the east coast of Italy, where he arrived to find nearly no one. Two Venetian ships arrived on August 11. Pius died during the night of August 14–15. His heart was interred at Ancona, still facing, as it were, the infidel East. His body was taken to Rome and there buried in St. Peter's; it was transferred to the Church of San Andrea della Valle when the new St. Peter's was being built.

Pope Pius II's great knowledge of conditions in Germany and elsewhere inspired a scheme of wide church reform, but the political conditions of the time and the resistance of the various vested interests rendered its application impossible. He did what he could, particularly by encouraging the movements toward strict observance of the rules of life within religious orders. On the whole, he created worthy cardinals, and on Jan. 17, 1460, he issued a bull condemning appeals from a pope to a general (ecumenical) council of the church. A voluminous writer about the events he had participated in, he wrote also general history and geography, poetry, and at least one scurrilous novel (The Tale of Two Lovers). Pius II was a patron of humanists, and he commissioned the architect Bernardo Rossellino (Rossellino, Bernardo) to transform his native village of Corsignano into the town of Pienza. Rossellino's buildings and town plan in Pienza represent one of the earliest examples of Renaissance urban planning.