While the fifteenth and sixteenth centuries were a time when Italian painters expanded their repertoire to include historical events, independent portraits and mythological subject matter, Christianity retained a strong hold on their careers. Most works of art from this era are sacred. While the range of religious subject matter included subjects from the Old Testament and images of saints whose cults date after the codification of the Bible, the Madonna remained a dominant subject in the iconography of the Renaissance.

Some the most famous Italian painters to turn to this subject are Leonardo da Vinci, Michelangelo and Raphael, Giorgione, Giovanni Bellini and Titian, in the 16th century. They developed on the foundations of fifteenth century Marian images by Fra Angelico, Fra Filippo Lippi, Mantegna and Piero della Francesca in particular, among countless others. The subject was equally popular in Early Netherlandish painting and that of the rest of Northern Europe.

The subject retaining the greatest power on all of these men remained the maternal bond, even though other subjects, especially the Annunciation, and later the Immaculate Conception, led to a greater number of paintings that represented Mary alone, without her son. As a commemorative image, the Pietà became an important subject, newly freed from its former role in narrative cycles, in part, an outgrowth of popular devotional statues in Northern Europe. Traditionally, Mary is depicted expressing compassion, grief and love, usually in highly charged, emotional works of art even though the most famous, early work by Michelangelo stifles signs of mourning. The tenderness an ordinary mother might feel towards her beloved child is captured, evoking the moment when she first held her infant son Christ. The spectator, after all, is meant to sympathize, to share in the despair of the mother who holds the body of her crucified son.

There are a large number of articles on individual works of various sorts in Category:Depictions of the Virgin Mary and its Sub-category. The term "Madonna" is sometimes often to representations of Mary that were not created by Italians.

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