The basilica is one of the masterpieces of Renaissance architecture. Its construction was commissioned by Ludovico III Gonzaga in 1472, based on designs by Leon Battista Alberti, but it was only completed 328 years later.

The church’s façade features prominent classical elements: a temple front, a triumphal arch, and a basilica layout. The church was built to receive pilgrims coming to see the reliquary believed to contain the blood of Christ, preserved in a crypt beneath a hole in the floor directly under the dome. This relic, called Preziosissimo Sangue di Cristo (The Most Precious Blood of Christ), was brought to the city by the Roman soldier Longinus, who collected drops of blood from the ground at the foot of the cross.

To allow all worshippers to see the holy relic, Alberti designed the church without supporting columns, creating a single large nave with an impressive barrel vault above. The church walls are decorated with paintings that create an optical illusion of cladding.