Leonardo, Michelangelo and Raphael worked in Florence early in the sixteenth century, but had all left by 1508. Andrea del Sarto became the city's most important painter: his rich colouring and tender expressiveness epitomised the Florentine High Renaissance style. His pupils Pontormo and Rosso Fiorentino developed the style later known as Mannerism. Trained by Pontormo, Bronzino became a leading court artist to the ruling Medici, producing sophisticated portraits. Giorgio Vasari, best known today for his vivid biographies of fellow artists was also in Medici service.

In Rome, Pope Julius II commissioned the two defining masterpieces of the High Renaissance: Michelangelo's Sistine ceiling and Raphael's decoration of the papal apartments (the Stanze). Raphael's workshop produced a generation of artists capable of producing complex decorative schemes such as Polidoro da Caravaggio; Perino del Vaga and Giulio Romano. In 1527 the Imperial troops of Charles V sacked Rome, and many artists and patrons fled the devastated city.