The XV-XVI Century Art Department took its current form in 2008. Still, its origins date back to 1932, when the then Monuments, Museums, and Pontifical Galleries collections were divided into three sections, including the Medieval-Modern section, entrusted in 1933 to the direction of Deoclecio Redig De Campos. In 1971 the Museums were subdivided into Departments, and the Department for Medieval and Byzantine Art was established, directed starting the same year by Fabrizio Mancinelli. Upon the latter's death in 1994, the Department was entrusted to Arnold Nesselrath, who was in charge until 2017 and then replaced by Guido Cornini (who died prematurely in 2022).

The artistic heritage under the Department's responsibility includes pictorial and architectural complexes of extraordinary historical and cultural significance, including, to name but a few, the frescoes of the Sistine Chapel, with the scenes commissioned by Pope Sixtus IV and executed between 1481 and 1482 by Sandro Botticelli, Domenico Ghirlandaio, Pietro Perugino, Cosimo Rosselli, and Luca Signorelli, up to the vault and altar wall with the Last Judgment, created by Michelangelo at the time of Julius II and Paul III; the Raphael Rooms, frescoed by the Urbino master and his pupils between 1508 and 1524; the Gallery of Maps, a 120-meter corridor decorated in the years of Gregory XIII (1572-1585) under the direction of Girolamo Muziano and Cesare Nebbia; the Niccoline Chapel, frescoed under Nicholas V by Beato Angelico (1448-1450); and the Borgia Apartment, commissioned by Alexander VI and frescoed by Pinturicchio between 1492 and 1494.

The Department also has the task of protecting and enhancing the Vatican Pinacoteca's collection of paintings from the 15th and 16th centuries, including several masterpieces by such masters as Beato Angelico, Filippo Lippi, Melozzo da Forlì, Carlo Crivelli, Giovanni Bellini, Perugino, Leonardo, Raphael, Giulio Romano, Titian, Veronese, and many others.