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The fame of the David spread quickly, and in 1505, Pope Julius II asked Michelangelo to come to Rome to design his tomb. The Tomb of Julius project, which was nagged by the need for numerous redesigns and contract issues, took nearly forty years to complete, and Michelangelo considered the project the tragedy of his career. The elaborate tomb was originally intended to be part of the new St. Peter's church being constructed in Rome by the architect Bramante, a project that Michelangelo later took over. However, in his initial contract negotiations for the tomb, Michelangelo began to suspect that the Pope was giving preferential treatment to Bramante and the artist Raphael, and in 1506 Michelangelo left Rome in a huff to return to Florence.

In Florence, Michelangelo resumed work on the projects he had left behind when he departed for Rome. A few months later, Michelangelo went to Bologna to meet again with the Pope, who was waging a military campaign against the city. They discussed the tomb further, and Michelangelo cast a large bronze portrait of Julius that was later destroyed. In 1508, the Pope had Michelangelo stop work on the tomb and begin painting the ceiling of the Sistine Chapel. Michelangelo, annoyed at the disruption, wanted to finish the difficult work of painting the enormous ceiling as quickly as possible. He finished in an amazing four years, in 1512, pausing once in 1510 to complain to the Pope in Bologna. The complexity of the finished masterpiece and its interrelated perspectival views is staggering–hundreds of Biblical figures painted in luminous colors and robust chiaroscuro make up twenty-five scenes describing the beginning of the world. Michelangelo, in characteristic fashion, claimed that the design was all his own, but most likely he was assisted by Biblical scholars assigned by Pope Julius II. Around this time, Michelangelo also began writing poetry on a semi-regular basis.

In 1512, the Medicis regained control of Florence with the help of Spanish military forces, ending the short-lived republic and imposing the autocratic rule of Giovanni and Giuliano de' Medici upon the city. In 1513, Pope Julius II died, and Giovanni de' Medici, the son of Lorenzo "The Magnificent" and Michelangelo's childhood friend, succeeded Julius as Pope Leo X. The death of Julius further complicated the contract issues over his tomb, and Michelangelo deliberated with the Pope's heirs over a revised contract. From 1513 to 1516 Michelangelo worked on carving the massive Moses figure for Julius's tomb, which was to become its centerpiece. He also began work on the statues of two Slaves, although these were never finished and never actually became part of the finished tomb itself. The monumental Moses is one of the absolute high points of Michelangelo's sculptural career. It is the only figure in the finished project that was certainly executed by Michelangelo himself rather than his assistants, whom he eventually assigned to finish the disastrous project. The two slave statues, the Dying Slave and the Rebellious Slave, while both unfinished, are elegant expressions of Michelangelo's obsession with the tense sensuality of the nude male figure and with the physical energy imprisoned within.

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