Back in Florence in 1485, Ghirlandaio painted fresco cycles in the Sassetti chapel of S. Trinita for the donor and banker Francesco Sassetti, who became manager of the branch of the Medici bank in Genoa, only to be replaced by Giovanni Tornabuoni -- Ghirlandaio's future patron. In the chapel, Domenico painted six scenes from the life of St Francis, including St Francis obtaining from Pope Honorius the Approval of the Rules of his Order; Death and Obsequies, and Resuscitation, by the interposition of the beatified saint, of a child of the Spini family, who had been killed by falling out of a window. In the first work appears a portrait of Lorenzo de Medici; and in the third, the painter's own likeness, which he also included in one of his pictures in S. Maria Novella as well as in the Adoration of the Magi in the orphanage called the Ospedale degli Innocenti. The altarpiece from the Sassetti chapel, the Adoration of the Shepherds, is now in the Florentine Academy.
Immediately after this commission, Ghirlandaio was asked to renew the frescoes in the choir of S. Maria Novella, which formed the chapel of the Ricci family, but the Tornabuoni and Tornaquinci families, then much more prominent than the Ricci, undertook the cost of the restoration, with conditions; the question of preserving the arms of the Ricci gave rise to some amusing litigation. The frescoes, by Domenico and many assistants, were painted in four courses along the three walls, the main subjects being the lives of the Madonna and St. John the Baptist. These works are particularly interesting in that they include many historical portraits, a genre in which Ghirlandaio was preeminently skilled.
Ghirlandajo's series on the life of Mary, executed with utmost attention to realistic detail, seems to represent domestic scenes from contemporary life of the Florentine nobility, rather than historical events of cosmic significance.In this cycle, there are no fewer than twenty-one portraits of the Tornabuoni and Tornaquinci families: in the Angel appearing to Zacharias, portraits of Politian, Marsilio Ficino, and others; in the Salutation of Anna and Elizabeth, the beautiful Ginevra de Benci; in the Expulsion of Joachim from the Temple, Mainardi and Baldovinetti (or the latter figure may, perhaps, be Ghirlandaio's father). The Ricci chapel was completed in 1490; the altarpiece was probably executed with the assistance of Domenico's brothers, Davide and Benedetto; the painted window was from Domenico's own design.
Other distinguished works from Ghirlandaio's hand are an altarpiece in tempera of the Virgin Adored by Sts Zenobius, Justus and others, painted for the church of St Justus, but now in the Uffizi gallery, a remarkable masterpiece; Christ in Glory with Romuald and other Saints, in the Badia of Volterra; the Adoration of the Magi, in the church of the Innocenti (already mentioned), perhaps his finest panel-picture (1488); and the Visitation (Louvre) which bears the latest ascertained date (1491) of all his works. Ghirlandaio did not often attempt the nude; one of his pictures including nudes, Vulcan and his Assistants forging Thunderbolts, was painted for Lo Spedaletto, but (like several others specified by Vasari), no longer exists. The mosaics that he produced date before 1491; one, of special note, is the Annunciation, on a portal of the cathedral of Florence.