Pius IV entrusted Michelangelo Buonarroti, an artist of great prestige who at the time was working at Saint Peter's, to transform the Thermal Baths into a church.

The great master had much input especially in the transept area. He created a Greek cross design leaving unchanged several right-angle frames, the vestibule (former nymphaeum passage towards the calidarium) and the chancel (frigidarium). As a result, there were three entrances: two on the sides of the transept and one towards the exedra. The works began immediately and were continued after Michelangelo's death (1564) by the nephew of Antonio Lo Duca, Jacopo, assistant and pupil of the geat Florentine master. The works ended in mid-18 th Century when the entrances to the left were closed by the Chapel of Saint Bruno (side of Via Cernaia) designed by Carlo Maratta and on the right by the Chapel dedicated to Niccolò Albergati, created by the architect Clemente Orlandi. The latter began to lay out and arrange the first large paintings from the Vatican Basilica.