On that date began a period of conflict known as the wars of Italy, at which the peninsula was conquered by foreign powers and on the Italian territory alternated the expansionist ambitions of France and Spain.

Already the end of 1400 was signed by the descent into Italy by Charles VIII, king of France, who sought to conquer the Kingdom of Naples, but he failed in the enterprise because the same Italian cities that had favored the action, including the Duchy of Milan, then ruled by Ludovico il Moro, did not adequately support his conquests.

During the 1500's the ambitions of conquest of France and Spain, who competed in the long domination over the Italian territory, characterize the political life of fragmented territorial realities of the peninsula. The contrasts between the two powers lasted until 1559, when it was signed the Peace of Cateau - Cambresis and which is generally referred to as the conclusion of the Italian Renaissance, coinciding with the beginning of Spanish domination.

Spain consolidated its position because the Italian dominion was destined to last until 1714, the year of termination of the War of Spanish Succession and the beginning of the hegemony of Austria.

During the Spanish rule, which lasted throughout the second half of 1500 and during the 1600s, Spain exercised direct rule over the whole island and southern Italy and the Duchy of Milan. The Grand Duchy of Tuscany and the Republic of Genoa were in fact forced to support the imperial policy, while the Duchy of Savoy, situated geographically between the Spanish dominions in Italy and the French territory, in fact became a battleground for the two powers.