From approximately the 4th through the 13th centuries mosaics dominated European mural decoration, reaching an unsurpassed peak of richness and color in Early Christian Art and, especially, Byzantine Art. The notable centers of mosaic production were Ravenna, Italy, and Constantinople (now Istanbul), where Byzantine artists perfected a stately, hieratical, and two-dimensional style that influenced almost all forms of pictorial expression in medieval Europe. The dethronement of mosaic as the preeminent medium of European mural art occurred in 14th-century Italy, where fresco was reborn in the genius of Giotto and Simone Martini. In Giotto's Arena Chapel frescoes (c.1305, Padua) the pictorial depth and narrative interest of classical art returned to mural painting, banishing the static flatness of mosaic art. Giotto's revolution in mural art was carried on and broadened by the great fresco painters of the Early Renaissance period (c.1420-1500), the most notable of whom were Fra Angelico, Masaccio, and Piero Della Francesca. The high point of Renaissance fresco—and one of the greatest expressions of mural art—came in a brief span of 20 years (1495-1515), with the unparalleled freedom and beauty of Leonardo Da Vinci Last Supper (1495-98; Santa Maria delle Grazie, Milan), Raphael's School of Athens (1510-11; Stanza della Segnatura, Vatican); and Michelangelo's Sistine Chapel ceiling (1508-12). Throughout the remainder of the 16th century, Italian Late Renaissance and Mannerist painters such as Paolo Veronese and Giulio Romano experimented with illusionistic ceiling and wall frescoes that emphasize technical virtuosity.

During the baroque period of the 17th century, fresco gave way to panel painting in mural art, and dramatic, exuberant wall decorations such as Peter Paul Rubens's Marie de Medici cycle (1622-25; Louvre, Paris) filled the palaces and villas of northern Europe. The kinetic drama of baroque wall painting was followed by the bold romanticism of Eugene Delacroix's murals for Saint Sulpice (1856-61) and the Louvre (1850-51) in Paris. Mural painting generally declined in importance during the 19th century, although neo-Gothic movements such as the English Pre-Raphaelites and the German Nazarenes resurrected some forms of medieval mural art. Modern interest in this ancient art form was rekindled, however, by the murals executed in the 1890s for the 1893 Chicago World's Fair—by Mary Cassatt, Kenyon Cox, and others—and the Boston Public Library – by Pierre Puvis de Chavannes, John Singer Sargent, and others. These public works led directly to the three major movements that have dominated 20th-century mural painting: the Mexican muralists of the 1920s and '30s, the American muralists of the 1930s and early '40s, and the outdoor-urban muralists of the contemporary era.

The Mexican muralists, especially Diego Rivera, Jose Clemente Orozco, and David Alfaro queirossi, used fresco and other mural techniques to express revolutionary themes. Rivera's work in the United States influenced Depression-era American artists, who, between 1935 and 1943, created hundreds of murals for public buildings under government-sponsored art programs. Great freedom and variety characterized the work of such muralists as Stuart Davis and Ben Shahn and of the American regionalist Thomas Hart Benton. The influence of the muralists of the 1930s has been carried over into new schools of mural painting, beginning with the ghetto and counterculture urban wall painters of the 1960s and '70s and the graffiti artists whose work began to receive serious attention in the 1970s. The tradition of amateur mural making in neighborhoods lives on, while contemporary professional muralists are commissioned by entities ranging from municipalities to corporations.