The Catacombs of San Callisto are the best known of the Roman catacombs and the first official underground burial site for early Christians, including many second- and third-century martyrs. It was probably Calixtus who was chiefly responsible for the Church becoming the legal owner of the cemeteries. Calixtus was appointed administrator of the cemetery which bears his name by pope Zephyrinus. In 217 he succeeded Zephyrinus as pope and five years later he died.

Excavations have revealed five different levels of loculi, niches where the bodies, wrapped in sheets, were placed in tiers. The openings to the loculi were closed with slabs of marble, but these have long since disappeared, as have any artifacts of value. A major attraction is the papal crypt with the remains of several martyred early popes. Nearby, with its Byzantine frescoes, is the Cubiculum of St. Cecilia, whose body was discovered here by Pope Paschal I and moved to Santa Cecilia in Trastever. Other cubicles have frescoes and Christian symbols carved on the walls. In the crypt of St. Eusebius is a sarcophagus containing two mummified bodies.