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Founded in 1256 by the Umiliati, a wool-weaving sect of the Benedictines whose trade helped establish this area as a textile district, the present Ognissanti was rebuilt by its new Franciscan owners in the 17th century. It has the earliest baroque facade in Florence, designed by Matteo Nigetti in 1627 and rebuilt in travertine in 1872.

Ognissanti was the parish church of the Vespucci family, agents of the Medici bank in Seville. A young Domenico Ghirlandaio portrayed several of the family members in his Madonna della Misericordia (1470) on the second altar to the right. The lady under the Madonna's left hand may be Simonetta Vespucci, renowned beauty of her age, mistress of Giuliano de' Medici (Lorenzo's brother), and the possible model for Venus in Botticelli's Birth of Venus. The young man with black hair to the Madonna's right is said to be Amerigo Vespucci (1454-1512), whose letters about exploring the New World in 1499 and again from 1501 to 1502 would become so popular that a cartographer used a corruption of Amerigo's name on an influential set of maps to describe the newly discovered continent. The family tombstone (America's namesake rests in peace underneath) is to the left of this altar.

Between the third and fourth altars is Botticelli's fresco of a pensive St. Augustine in His Study (1480), a more intense work than its matching St. Jerome in His Study by Ghirlandaio across the nave. Botticelli, whose real name was Sandro Filipepi, is buried under a round marker in the second chapel in the right transept. You can enter the convent to the left of the church facade at Borgo Ognissanti 42. In the refectory here is Domenico Ghirlandaio's Last Supper, or Cenacolo, painted in 1480 with a background heavy on Christian symbolism.