In 1494, there were five sovereign regional powers in Italy: Milan, Venice, Florence, the Papal States and Naples. In 1536, only one remained: Venice. These decades of conflict precipitated great anxiety among Western thinkers, and Italians responded to the fragmentation, forevermore, of Latin Christendom, the end of self-governance for Italians, and the beginning of the early modern era in a myriad of ways. They were always heavily influenced by the lived experience of warfare between large Christian armies on the peninsula.

The diplomatic and military history of this 30-year period was a complex situation that one eminent Renaissance historian, Lauro Martines, has described as "best told by a computer, so many and tangled are the treatises, negotiations and battles." At the same time, the fighting went in tandem with the Renaissance and was influenced by it. Most historians credit the city-state of Florence as the place that started and developed the Italian Renaissance, a process carried out through the patronage and commission of artists during the late 12th century. If Florence is receiving its due credit, much of it belongs to the Medicis, the family dynasty of Florence that ruled at the height of the Renaissance. The dynasty held such influence that some of its family members even became Pope.

Meanwhile, plans for a French invasion were years in the making, and France's young King Charles VIII, heavily influenced by chivalric tales and his men of finance, had begun his preparations for conquering Naples as a base from which to launch a crusade in 1491. Two key events were the catalysts for these plans. The first was the arrival of Cardinal Giuliano della Rovere at Avignon in May 1494.