The year 1500 was a turning point: while under rule of Ludovico il Moro, the city fell under the attacks of the army of Louis XII of France led by Gian Giacomo Trivulzio. The city was contested by France and the Valois on one side and by the Hapsburgs of Austria and Spain on the other. The Spanish domination (1535-1713), began with the victory of Charles V and marked a period of cultural and economic oppression.
During this period there was an increase in the power of the clergy, especially the figures of Carlo Borromeo, archbishop from 1565 to 1584 and Federico Borromeo archbishop from 1595 to 1631.
Another noteworthy year was 1630, when the city was devastated by the plague described by Manzoni.