Hatshepsut, the elder daughter of the 18th-dynasty king Thutmose I and his consort Ahmose, was married to her half brother Thutmose II, son of the lady Mutnofret. Since three of Mutnofret's older sons had died prematurely, Thutmose II inherited his father's throne about 1492 BC, with Hatshepsut as his consort. Hatshepsut bore one daughter, Neferure, but no son. When her husband died about 1479 BC, the throne passed to his son Thutmose III, born to Isis, a lesser harem queen. As Thutmose III was an infant, Hatshepsut acted as regent for the young king.

For the first few years of her stepson's reign, Hatshepsut was an entirely conventional regent. But by the end of his seventh regnal year, she had been crowned king and adopted a full royal titulary (the royal protocol adopted by Egyptian sovereigns). Hatshepsut and Thutmose III were now corulers of Egypt, with Hatshepsut very much the dominant king. Hitherto Hatshepsut had been depicted as a typical queen, with a female body and appropriately feminine garments. But now, after a brief period of experimentation that involved combining a female body with kingly (male) regalia, her formal portraits began to show Hatshepsut with a male body, wearing the traditional regalia of kilt, crown or head-cloth, and false beard. To dismiss this as a serious attempt to pass herself off as a man is to misunderstand Egyptian artistic convention, which showed things not as they were but as they should be. In causing herself to be depicted as a traditional king, Hatshepsut ensured that this is what she would become.

Hatshepsut never explained why she took the throne or how she persuaded Egypt's elite to accept her new position. However, an essential element of her success was a group of loyal officials, many handpicked, who controlled all the key positions in her government. Most prominent amongst these was Senenmut, overseer of all royal works and tutor to Neferure. Some observers have suggested that Hatshepsut and Senenmut may have been lovers, but there is no evidence to support this claim.

Traditionally, Egyptian kings defended their land against the enemies who lurked at Egypt's borders. Hatshepsut's reign was essentially a peaceful one, and her foreign policy was based on trade rather than war. But scenes on the walls of her Dayr al-Baḥrī temple, in western Thebes, suggest that she began with a short, successful military campaign in Nubia. More-complete scenes show Hatshepsut's seaborne trading expedition to Punt, a trading centre (since vanished) on the East African coast beyond the southernmost end of the Red Sea. Gold, ebony, animal skins, baboons, processed myrrh, and living myrrh trees were brought back to Egypt, and the trees were planted in the gardens of Dayr al-Baḥrī.

Restoration and building were important royal duties. Hatshepsut claimed, falsely, to have restored the damage wrought by the Hyksos (Asian) kings during their rule in Egypt. She undertook an extensive building program. In Thebes this focused on the temples of her divine father, the national god Amon-Re (see Amon). At the Karnak temple complex, she remodeled her earthly father's hypostyle hall, added a barque shrine (the Red Chapel), and introduced two pairs of obelisks. At Beni Hasan in Middle Egypt, she built a rock-cut temple known in Greek as Speos Artemidos. Her supreme achievement was her Dayr al-Baḥrī temple; designed as a funerary monument for Hatshepsut, it was dedicated to Amon-Re and included a series of chapels dedicated to Osiris, Re, Hathor, Anubis, and the royal ancestors. Hatshepsut was to be interred in the Valley of the Kings (Kings, Valley of the), where she extended her father's tomb so that the two could lie together.

Toward the end of her reign, Hatshepsut allowed Thutmose to play an increasingly prominent role in state affairs; following her death, Thutmose III ruled Egypt alone for 33 years. At the end of his reign, an attempt was made to remove all traces of Hatshepsut's rule. Her statues were torn down, her monuments were defaced, and her name was removed from the official king list. Early scholars interpreted this as an act of vengeance, but it seems that Thutmose was ensuring that the succession would run from Thutmose I through Thutmose II to Thutmose III without female interruption. Hatshepsut sank into obscurity until 1822, when the decoding of hieroglyphic script allowed archaeologists to read the Dayr al-Baḥrī inscriptions. Initially the discrepancy between the female name and the male image caused confusion, but today the Thutmoside succession is well understood.