Before speaking about a work of such great importance as the Sistine Chapel it is necessary to say a word about the Pope who commissioned it. Pope Sixtus V, more than any of his predecessors, knew how to reinvigorate the impoverished city from the "Sack" of Rome of 1527. His first concern was to give back to the Eternal City the possibility of expansion by restoring unsound areas and creating useful infrastructures for the utilization of newly settled neighborhoods. The Pope commissioned his trusted architect, Domenico Fontana, to construct a chapel of the Most Blessed Sacrament which could also house the Nativity scene.

The iconographic design of the paintings, which represent the ancestors of Christ as well as stories of the Virgin and the life of Jesus, lies in the Chapel  of the Nativity under the altar that preserves the ancient Nativity Oratory, which was constructed in the XIIIth century by Arnolfo di Cambio. The paintings of the Sistine Chapel celebrate the triumph of the Virgin, whose divine maternity had been denied by the Protestant heresies, to which the Council of Trent responded. The work was directed by Cesare Guerra and Giovanni Nebbia, who would receive the financing for the project between 1587 and 1589. Their principle interest was to make sure that the figures of the Sistine Chapel were a natural continuation of the message already expressed in the mosaics in the apsidal arch.

Stylistically the paintings in the Sistine Chapel easily capture the eye of the observer. Eliminating all intellectualism and personal artistic style, the images are clear and recognizable without the need for further explanation. Many artists worked on the Sistine Chapel.

Sixtus went personally to see the work in the studio of the artists and was present at the chapel's erection in June of 1587. Giovanni Antonio Paracca, known as Valsoldo, sculpted the statue of Sixtus V, which represents the pontiff on his knees serenely gazing upon the Tabernacle and the Crib of the Nativity. The altar in the center of the chapel is very beautiful: four gold leafed bronze life-size angels by Sebastiano Torregiani hold up the ciborium, which is a model of the actual chapel, richly decorated with angels and prophets in full relief with a bas-relief on the doors. At the foot of the altar, at the end of the double staircases of the Confession that leads to the Nativity Oratory, is the Nativity by Cecchino of Pietrasanta from the XVIth century and above, an altar in the cosmatesco style.