While still working on the Last Judgment, Michelangelo received yet another commission for the Vatican. This was for the painting of two large frescos in the Cappella Paolina depicting significant events in the lives of the two most important saints of Rome, the Conversion of Saint Paul and the Crucifixion of Saint Peter. Like the Last Judgment, these two works are complex compositions containing a great number of figures. They were completed in 1550. In the same year, Giorgio Vasari published his Vita, including a biography of Michelangelo.

In 1546, Michelangelo was appointed architect of St. Peter's Basilica, Rome. The process of replacing the Constantinian basilica of the 4th century had been underway for fifty years and in 1506 foundations had been laid to the plans of Bramante. Successive architects had worked on it, but little progress had been made. Michelangelo was persuaded to take over the project. He returned to the concepts of Bramante, and developed his ideas for a centrally planned church, strengthening the structure both physically and visually. The dome, not completed until after his death, has been called by Banister Fletcher, "the greatest creation of the Renaissance".

As construction was progressing on St Peter's, there was concern that Michelangelo would pass away before the dome was finished. However, once building commenced on the lower part of the dome, the supporting ring, the completion of the design was inevitable.