In 336, Pope Mark built a church devoted to one of the Evangelists, his name bearer St. Mark, in a place called ad Pallacinas. The church is thus recorded as Titulus Marci in the 499 synod of Pope Symmachus. [At that time it became one of the stational churches of the city (Monday of the third week in Lent)].
After a restoration in 792 by Pope Adrian I, the church was rebuilt by Pope Gregory IV in 833. Besides the addition of a Romanesque bell tower in 1154, the major change in the architecture of the church was ordered by Pope Paul II in 1465-70, when the façade of the church was restyled according to the Renaissance taste with a portico and loggia, using marbles taken from the Colosseum and the Theatre of Marcellus. The façade is attributed to Leon Battista Alberti. Paul II being a Venetian by birth, assigned the church to the Venetian people living in Rome.
The last major reworking of the basilica was started in 1654-57 and completed by Cardinal Angelo Maria Quirini in 1735-50. With these restorations, the church received its current Baroque decoration.