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.

Lorenzo de Medici may have not been a king, prince or duke, but he nevertheless held significant influence over all of the noble houses of the region, from Milan and Naples to the king of France. Between 1482 and 1484, Lorenzo's influence prevented a close alliance between King Louis IX of France and the city of Venice, which was at war with Ferrara. Lorenzo's personal influence helped reduce Venice's power in the region. During the Baron's War of 1485 and 1486, while Florence sided with the pope, Lorenzo favored Ferdinando of Aragon, who had close ties with Naples, giving Lorenzo the chance to attempt to negotiate an improvement in relations between the pope and Naples. While the two had once been allied against Florence, their alliance had ended with the war. Lorenzo proposed a new agreement between the two, largely centered around financial obligations, in 1489. It was accepted in 1492, creating an enduring peace for some time. Perhaps fittingly, once Lorenzo the Magnificent died, the tenuous peace would go with him, touching off the Italian Wars.

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. The holder of the see at Vincula, Giuliano della Rovere, and Rodrigo Borgia quarreled upon the latter's election to the Papal throne as Pope Alexander VI.[3] After months of intrigue and a failed assassination plot, della Rovere sailed from Ostia to France, where he joined his voice to the chorus inciting Charles VIII to war. Giuliano della Rovere's connections in his native Genoa made him a formidable ally in that he was able to help the French king raise the necessary funds for an invasion from Ligurian moneylenders.

The French invasion of Italy in 1494 was shocking to Italian observers both in terms of scale and ferocity, and various Italian powers' attempts to expel the French from the peninsula would culminate with the Battle of Fornovo, which turned out merely to be the first major battle in a long series of conflicts.