Later a church devoted to the Twelve Apostles was built, which was in turn flanked and replaced by a new cathedral dedicated to Saint Lawrence, in Romanesque style.

The first cathedral, now the basilica of St. Syrus, was founded probably in the 5th or 6th century AD, devoted to Saint Sirus, bishop of Genoa.

In 1550 the Perugian architect Galeazzo Alessi was commissioned by the city magistrates to plan the reconstruction of the entire building; however, he executed only the covering of the nave and aisles, the pavement, the dome and the apse.

The present 7 bells are tuned in the major scale of C. Among the artworks inside the church are ceiling frescoes in a chapel on the north by Luca Cambiaso; a Crucifixion with Saints (St. Sebastian's Vision) by Barocci; in front of the organ is an Episode from the life of St. Lawrence by Giovanni Andrea Ansaldo; the ceiling fresco in the presbytery of the Martyrdom of St Lawrence was painted by Lazzaro Tavarone; and an Assumption of the Virgin (1914) by Gaetano Previati.

Among the most important pieces are the Sacro Catino brought by Guglielmo Embriaco after the conquest of Caesarea and supposed to be the chalice used by Christ during the Last Supper; the Cassa Processionale del Corpus Domini ; and the Zaccaria Cross, a Byzantine reliquary that holds supposed relics of the True Cross.

Because of a crew error the British battleship HMS Malaya fired a 381 mm (15.0 in) armour-piercing shell into the south-eastern corner of the nave.