In a letter from him to Piero di Cosimo de' Medici, dated from Perugia in 1438, where he likewise resided for many years, he mentions his long connection with the fortunes of the Medici family, and begs to be allowed to paint an altarpiece for the head of that house.

Between 1439 and 1441 he painted a masterpiece of the Adoration of the Magi, a round panel which was probably commissioned for the palace of the wealthy Medici family and is now in Berlin.

He worked at the decorations of the Portinari chapel in the hospital of Santa Maria Nuova in Florence from 1439–1445, and had as his assistants Piero della Francesca and Bicci di Lorenzo.

It is certain that whilst employed there he used linseed oil as his medium, since the hospital books of that date make many allusions to this item in his expenses.

The predella included panels with scenes of the saints of the main composition, and a central, double-size Annunciation: the Stigmata of St. Francis and John Baptist in the Desert are currently in the National Gallery of Art in Washington, the Annunciation and The Miracle of St. Zenobius are in the Fitzwilliam Museum of Cambridge, and the Martyrdom of St. Lucy is in the Berlin State Museums.