The Department of XV-XVI Century Art took on its present form in 2008, with the implementation of Title IV of the new Internal Regulations of the Museums, which came into force on 1 October of that year (Regulations of the Directorate of the Museums, Vatican City), with the task of studying, safeguarding and promoting the “collections of 15th and 16th century paintings and statuary exhibited in the Pinacoteca, the Galleries, the Vatican Palaces, preserved in the storerooms or placed as furnishings in the papal representations or in extra-territorial properties of Vatican City State”. The Department is also responsible for “wall paintings and decorations pertaining to monuments of a historical and artistic nature" from the same time period, entrusted to the Directorate of the Museums and Cultural Heritage.

The origins of the Department date back to 1932 when, following the Law and Regulations of 1 and 5 December, the collections of the then Monuments, Museums and Pontifical Galleries were divided into three sections, including the Medieval-Modern one, entrusted in 1933 to the direction of Deoclecio Redig De Campos (1905-1989). In 1971, when the Museums were divided into Departments following the entry into force of the new Regulations, the Byzantine, Medieval and Modern Art Department was established, and from the same year was directed by Fabrizio Mancinelli. When Mancinelli died in 1994, Arnold Nesselrath took over the direction of the Department, and remained in this role until 2017.

The artistic heritage within the purview of the Department includes pictorial and architectural complexes of extraordinary historical and cultural importance, such as the frescoes of the Sistine Chapel, from the panels on the walls with the Stories of Moses, Stories of Christ and Portraits of the Pontiffs commissioned by Pope Sixtus IV Della Rovere (1471-1484) and executed between 1481 and 1482 by masters of the calibre of Sandro Botticelli, Domenico Ghirlandaio, Pietro Perugino, Cosimo Rosselli and Luca Signorelli, to the ceiling with the Stories of Genesis in the centre up to the altar wall with the Last Judgement - works executed by Michelangelo at the time of Julius II Della Rovere (1503-1513) and Paul III Farnese (1534-1549) respectively; the Raphael Rooms (Room of the Segnatura, Room of Heliodorus, Room of the Fire in the Borgo and the Hall of Constantine), formerly part of the apartment on the second floor of the Pontifical Palace, inhabited by Pope Julius II and his successors and frescoed by the Urbino master and his pupils between 1508 and 1524; the Gallery of the Geographical Maps, a 120-metre corridor decorated during the years of Gregory XIII Boncompagni (1572-1585), under the direction of Girolamo Muziano and Cesare Nebbia and with the advice of the mathematician and geographer Ignazio Danti, with dozens of maps of the regions of Italy on the walls, of the four main Italian port cities (Civitavecchia, Genoa, Ancona and Venice) and two views of the Turkish siege of Malta in 1565 and the Battle of Lepanto in 1571 and, on the vault, various religious episodes that took place in the regions depicted on the walls below.

No less significant are the other two spaces included in the tour circuit of the Museums: the Niccoline Chapel, frescoed during the later years of Niccolò V Parentucelli (1447-1455) by Fra Angelico with the Stories of Saints Stephen and Lawrence on the walls and with figures of the Evangelists and Doctors of the Church on the vault (1448-50), and the Borgia Apartment, a series of rooms named after the controversial pontiff who lived there, the Catalan Alexander VI Borgia (1492-1503), notable for the sumptuous pictorial decoration by Pinturicchio and his workshop, who worked there between 1492 and 1494.

The Department is also responsible for a number of rooms of exceptional historical and artistic importance, whose particular location in the Palace and continuing liturgical and ceremonial use preclude the general public from seeing them. These are: the Pauline Chapel, reserved for the private worship of the Pontiff and frescoed by Michelangelo between 1542 and 1550, with the Conversion of Saul and the Crucifixion of St. Peter (Buonarroti's spiritual testament and the artist's last completed pictorial undertaking); the Sala Regia, begun by Perin del Vaga and decorated by artists such as Francesco Salviati, Orazio Samacchini, Livio Agresti, Giorgio Vasari, the Zuccari brothers and others between 1541 and 1573, approximately; the Ducal Hall, decorated between Pius IV Medici and Gregory XIII by a host of artists, the most important of whom were Lorenzo Sabatini and Raffaellino da Reggio, flanked by Cesare Piemontese, Matteo Brill, Paris Nogari and Matteino da Siena; the two Halls of Vestments and the related “Galleriola”, with frescoes by Mario Sabatini and Marco da Faenza (1576-77), among others, and a Pentecost by Girolamo Muziano (1576-78); the two Loggias by Giovanni da Udine, on the first and third floors of the Apostolic Palace; the same Loggia by Raphael and the Loggetta by Bibbiena, on the second and third floors of the same wing, parts of two separate decorative campaigns commissioned from the master of Urbino by Pope Leo X (1516-19) and Cardinal Dovizi da Bibbiena (1516) respectively; plus other rooms of high architectural and artistic value, connected to the very nature and identity of the Pontifical Palace. The Department has the task of supervising, researching and monitoring the state of conservation of all of these.

In addition to the above-mentioned responsibilities, the Department is also responsible for the care and promotion of the Vatican Pinacoteca's collection of 15th and 16th century paintings. Originating from two major bodies of work dating from 1770 and 1790, from the pontificates of Clement XIV Ganganelli (1769-1774) and his successor Pius VI Braschi (1775-1799) respectively, the Pinacoteca houses masterpieces by some of the leading masters of the Italian Renaissance, such as Fra Angelico, Filippo Lippi, Melozzo da Forlì, Carlo Crivelli, Giovanni Bellini, Perugino, Leonardo, Raphael, Giulio Romano, Titian, Veronese, Federico Barocci, Ludovico Carracci and many others.