Michelangelo's professional reputation developed through sculpture in Florence, Bologna and Rome. The Roman Pietà, completed around 1499, brought an ambitious treatment of anatomy and religious emotion to a prestigious commission. Returning to Florence, he carved David between 1501 and 1504 from a block already worked by another sculptor. Its placement beside the Palazzo Vecchio gave the biblical figure a civic meaning within the republic. His painting and sculpture drew on close study of the body and on drawing as a means of working out form and composition.

Pope Julius II summoned him to Rome in 1505 for a monumental tomb. Repeated changes, interruptions and disputes turned the project into a decades-long burden; the eventual monument included Moses but was much reduced from the first scheme. The Sistine Chapel ceiling, painted in 1508–1512, became another major undertaking. Stories from Genesis, prophets, sibyls and other figures occupy a complex painted architecture. The work required sustained technical organization and assistance even though Michelangelo's dominant role and individual designs shaped its character.

For Medici patrons he designed projects at San Lorenzo in Florence, including the New Sacristy and Laurentian Library. Changes in Florentine government and his work on fortifications during the republic's defence complicated those relationships. Settling permanently in Rome in the 1530s, he painted the Last Judgment on the Sistine altar wall, completed in 1541. Its immense gathering of bodies and forceful religious drama provoked admiration and controversy, particularly over nudity; alterations by other artists followed. His career depended on negotiating powerful patrons, political instability and commissions that often remained incomplete.

Architecture became increasingly central in later life. Designs for the Capitoline Hill and St Peter's transformed Roman civic and religious space; the basilica's dome was completed after his death with changes to his design. Poetry and correspondence reveal an intellectual life engaged with love, friendship, faith and the difficulties of artistic work. Late sculptures, including unfinished Pietàs, continued his investigation of suffering and form. He died in Rome in 1564 and was buried in Florence. His achievement crossed sculpture, painting and architecture, while the surviving drawings expose the revision and experiment behind works later celebrated as expressions of effortless genius.