The growing power of the King of Spain and Holy Roman Emperor Charles V alarmed Pope Clement VII, who perceived Charles as a threat to the papal power. Clement VII formed an alliance with Charles V's arch-enemy, King Francis I of France, which came to be known as the League of Cognac.^[4]

Apart from the Pope and the King of France, the League also included the Duchy of Milan, the Republic of Venice, the Republic of Genoa, and the Florence of the Medici. The League began hostilities in 1526 by attacking the Republic of Siena, but the undertaking proved to be a failure and revealed the weakness of the troops at the Pope's disposal.^[5]

The Imperial Army defeated the French army, but funds were not available to pay the soldiers. The 34,000 Imperial troops mutinied and forced their commander, Duke Charles III of Bourbon, to lead them towards Rome, which was an easy target for pillaging due to the unstable political landscape at the time.^{[citation needed]}

Aside from some 6,000 Spaniards under the Duke of Bourbon, the army included some 14,000 Landsknechte under Georg von Frundsberg; some Italian infantry led by Fabrizio Maramaldo, the powerful Italian cardinal Pompeo Colonna, and Luigi Gonzaga; and some cavalry under the command of Ferdinando Gonzaga and Philibert, Prince of Orange. Though Martin Luther himself was against attacking Rome and Pope Clement VII, some who considered themselves followers of Luther's Protestant movement viewed the papal capital as a target for religious reasons. Numerous outlaws, along with the League's deserters, joined the army during its march.^{[citation needed]}

The Duke of Bourbon left Arezzo on 20 April 1527, taking advantage of chaos among the Venetians and their allies after a revolt broke out in Florence against Pope Clement VII's family, the Medici. His largely undisciplined troops sacked Acquapendente and San Lorenzo alle Grotte, and then occupied Viterbo and Ronciglione, reaching the walls of Rome on 5 May.^{[citation needed]}