Architecture became Michelangelo's primary occupation in the last thirty years of his life, and once he had finally settled in Rome, he began to work on projects in earnest. Prior to the move, Michelangelo's architectural experience had been limited to the fa¸ade of San Lorenzo, the Florentine fortifications, and a few smaller commissions. In 1535, however, Pope Paul III designated Michelangelo as his primary painter, sculptor, and architect. Although this appointment was not immediately accompanied by any architectural assignments, it did discourage the heirs of Julius II from pestering Michelangelo over the uncompleted tomb and distracting him from other interests. From 1537 to 1539, while painting the Last Judgment, Michelangelo worked on the design for his most important civic architectural commission, the renovation and redesign of Rome's Campidoglio. He began by designing a base for a statue of Marcus Aurelius, which was situated in the middle of a symmetrical trapezoidal courtyard space, surrounded on three sides by newly designed fa¸ades. The massive size of these fa¸ades made the Campidoglio the most famous and influential civic center in the world. Michelangelo completed the design around 1545 or 1546, but the buildings were not completed until almost 100 years after his death.

In 1546, Michelangelo took over the construction of the Palazzo Farnese after the death of the previous architect, Giuliano da Sangallo. He also took over the design and construction of St. Peter's, which had gone through several different designs by Bramante, Raphael, and Sangallo. Michelangelo accepted no money for this project. He was able to compress the previous designs into an elegant, compact whole, with open spaces and a revolutionary upwardly thrusting dome, the model for which he finished in 1561. Michelangelo's design for the church came to serve as the standard for the architectural dome for hundreds of years after it was built by another architect in 1590, with some slight modifications.

In the final ten years of his life, Michelangelo work simultaneously on designs and models for St. Peter's, San Lorenzo, the conversion of the Roman Baths of Diocletian into the church of Santa Maria degli Angeli, a fa¸ade for the new city gate, and the Sforza Chapel in Santa Maria Maggiore. Michelangelo's architectural work was as revolutionary as his art, as evidenced by the indignant protests of his contemporaries, who were outraged by his break from Classical form and stability. In all his buildings, Michelangelo treated structural elements as being separate from decorative embellishments, and he was as concerned with creating open, flowing spaces as he was with sculptural details. His approach to architecture was always that of a sculptor to a block of marble–he sought to release the possibilities locked within a given space or location according to his personal conceptions of architecture rather than the rules of any school. Michelangelo stretched the limits of the Classical form to express his own aesthetic, thereby predicting the Baroque architecture of artists like Bernini and his contemporaries.

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