On 27 October 1480 Rosselli, together with other Florentine painters, left for Rome, where he had been called as part of the reconciliation project between Lorenzo de' Medici, the de facto ruler of Florence, and Pope Sixtus IV. The Florentines started to work in the Sistine Chapel as early as the Spring of 1481, along with Pietro Perugino, who was already there.
The theme of the decoration was a parallel between the stories of Moses and those of Christ, as a sign of continuity between the Old and the New Testament, as well as between the divine law of the Tables and the message of Jesus, who had chosen Peter (the first alleged bishop of Rome) as his successor: This would finally result in a legitimation of the latter's successors, the popes of Rome.
Due to the commission's size, the artists brought with them numerous assistants. Rosselli brought his son-in-law Piero di Cosimo. According to the Renaissance art historian Giorgio Vasari, Rosselli was considered one of the less gifted among the painters at the Sistine Chapel, and his paintings in the chapel were the subject of the other artists' irony. However, his sheer adoption of brilliant colors granted him the appreciation of the pope, who apparently, was not considered an art expert.