It was designed in the 16th century but the late Baroque facade was not finished until nearly a century later. It was built on the site of a previous church from the 4th century and dedicated to Pope Marcellus I, the church's patron saint who died in 309 AD, built over what was thought to have been his prison.
In 1519 a fire destroyed the earlier church, all that miraculously survived was a 15th century wooden cross which is now in the fourth chapel on the right.
In 1527, during the Sack of Rome decoration of the church was abandoned. In the fourth chapel are frescoes begun by Perino del Vaga, left unfinished the frescoes were later completed by Daniele da Volterra.