The relatively small number of paintings in the Duomo, as compared to the prevalent use of stained glass and sculptures, is justified by the basic decision reached at the beginning of the building work, to model the cathedral on the examples in European late Goth style.

The few surviving frescoes such as the Crucifix with the Madonna and saints, St. John the Baptist and Madonna of the Rose date from the first half of the 15th century and were painted by local painters. Large paintings were not commissioned until the second half of the 16th century, due to the Archbishop Carlo Borromeo's desire for reform: these were the altar-pieces for the altars designed for the lateral aisles and the panels or doors of the two organs.

In 1602, when Federico Borromeo was archbishop, two cycles of tempera paintings on canvas were begun: they depicted the Life and Miracles of San Carlo with the intention of paying homage the memory of the beatified Carlo Borromeo and press for his canonisation with a series of twenty very large paintings (for this reason now known as the Quadroni) illustrating the most significant episodes of his life.

In the 18th century another cycle of paintings was commissioned to enhance the ceremonial decoration of the Duomo: these were the canvases dedicated to the Stories of the Cross and of the Holy Nail, which are displayed in the presbytery enclosure during the annual celebration of the rediscovery of the Cross with the moving Rite of the Nivola, dating from the Borromeo era, during which the faithful express their devotion to the relic of the Cross preserved in the apse-conch of the Duomo.

For more information, see:
E. Brivio, Vita e miracoli di S.Carlo Borromeo. Itinerario pittorico nel Duomo di Milano, Milan, NED, 1995 G.A. Dell’Acqua, La pittura del Duomo di Milano, Milan, Veneranda Fabbrica del Duomo, 2001