All the work shows the importance of the influence of the Flemish school on Ghirlandaio, in particular the Portinari Triptych by Hugo van der Goes, taken by him to Florence in 1483 and now in the Uffizi.
The two side walls house the tombs of Francesco Sassetti and his wife Nera Corsi, under a gilded arch, a creation of Giuliano da Sangallo.
At the side of the altar are kneeling portraits of the two patrons, Nera Corsi on the left and Sassetti on the right: they direct their prayers towards the central altarpiece of the Adoration of the Shepherds, also by Ghirlandaio.
This scene is located on the upper left wall, and portrays the young Francis who having renounced all his assets by removing his clothes publicly, is protected by the bishop of Perugia.
The scene is set in Florence instead of Rome, the background showing the Piazza della Signoria, the Palazzo Vecchio and the Loggia dei Lanzi, which did not at that time contain statues).
The choice of the city was an allusion to the power and status that Florence had assumed; in Humanist circles it was considered a new Rome or Jerusalem.
A drawing, now in Berlin, shows that initially Ghirlandaio had intended a more traditional iconography following that of the frescoes in Santa Croce and without the portraits.
They are Giuliano, Piero and Giovanni, the future Pope Leo X, followed by other members of the Humanist Academy, Luigi Pulci and Matteo Franco.
The piece is rather similar to that of Giotto in Santa Croce with the sultan in the middle, St. Francis on the right with his brother friars, but with Ghirlandaio's innovation of a figure in the foreground whose back is to the observer.
The lower left wall represents St. Francis kneeling, with open arms, receiving the divine sign from an apparition of the crucified Christ supported by a group of cherubim.
The miracle portrayed occurred at La Verna, the castles of which can be seen in the background which is characterized by a naturalistic rendering of outstanding quality, including a well executed deer.
That the composition is derived from Giotto's work in Santa Croce is clearly seen in various elements including the monks' gestures, though Ghirlandaio added different details such as the monumental background and the varying responses of the different figures.
It portrays the resurrection of a boy who had died falling from Palazzo Spini Feroni, a palace on the piazza facing Santa Trinita.
Other figures portrayed on the right include Maso degli Albizzi, Angelo Acciaioli, Palla Strozzi and Neri di Gino Capponi.
The left city represents Rome, with the two sepulchres of the "prophetic" emperors, Augustus and Hadrian (who, at the time, was thought to be buried under the Torre delle Milizie).
The manger, before which the Child lies, is an ancient Roman sarcophagus with the inscription "Ense cadens soly mo Pompei Fulvi[us] augur Numen aitquae me conteg[it] urna dabit", an allusion of the coming of Christ through the prophecy of Fulvius, killed by Pompey the Great during the Roman conquest of Jerusalem.
Next to Mary is Saint Joseph looking upwards as, in the background, an angel is announcing to the shepherds the coming of Christ, while on the left, the long procession of the Magi is passing under a triumphal arch.