The original structure dates from 1100. It became the Church and Monastery of St. Mark in 1299, later passing under the protection of the Medici family in the early 15th century when Cosimo the Elder started using it regularly for his spiritual retreats. The church had been taken over by the Dominican friars a few years earlier and Cosimo gave Michelozzo the commission of restoring it (1436-43); he also carried out the fine sacristy as well as the splendid architectural solutions used inside the monastery for the corridor of cells and the library.

Fra Angelico, a friar and artist who, like Giotto, came from the Mugello, lived at the monastery during this period (from 1435) and carried out some of his finest works here. The Florentine Humanist Academy used to meet in the "Gardens" of St. Mark, while the refectory with its Last Supper was used first by Cosimo and later by Lorenzo the Magnificent to assemble some of the finest intellects of the time. This was where Fra Girolamo Savonarola preached and it is no surprise to find that Pico della Mirandola and Agnolo Poliziano, who both died in 1494, are buried here; their tombs are near the second altar on the left.

The church was later modified by Giambologna (Chapel Salviati) followed by Silvani two centuries later. The interior contains a fine altarpiece by Santi di Tito of St. Thomas offering to help at the Crucifix (first altar on the right), the Holy Conversation by Fra Bartolomeo of 1509 (second altar on the left). A Crucifix by Beato Angelico. An 18th century Madonna in Glory by Pucci is painted in the centre of the vast carved ceiling in the interior, designed with a single nave.
The Main Chapel is decorated with frescoes by Gherardini of the Glory of the Dominican Order (1717), while the Altar of Sant'Antonino on the left contains the embalmed body of the saint. On right the entrance of the S.Mark museum.