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.

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] 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.

With the death of their last respected leader, the common soldiery in the Imperial army lost any restraint when they easily succeeded in storming the walls of Rome the same day.

This group of 42, under the command of Hercules Goldli, managed to stave off the Habsburg troops pursuing the Pope's entourage as it made its way across the Passetto di Borgo, a secure elevated passage that connects the Vatican City to Castel Sant'Angelo.

Francesco Maria I della Rovere and Michele Antonio of Saluzzo arrived with troops on 1 June in Monterosi, north of the city.

On 6 June, Clement VII surrendered, and agreed to pay a ransom of 400,000 ducati in exchange for his life; conditions included the cession of Parma, Piacenza, Civitavecchia, and Modena to the Holy Roman Empire (however, only the last would actually change hands).

Often cited as the end of the Italian High Renaissance, the Sack of Rome impacted the histories of Europe, Italy, and Christianity, creating lasting ripple effects throughout European culture and politics.

[9] Before the sack, Pope Clement VII opposed the ambitions of Emperor Charles V. Afterward, he no longer had the military or financial resources to do so.

[11] Before the sack, Rome had been a center of Italian High Renaissance culture and patronage, and the main destination for any European artist eager for fame and wealth, thanks to the prestigious commissions of the papal court.

Pillaging finally ended in February 1528, eight months after the initial attack, when the city's food supply ran out, there was no one left to ransom, and plague appeared.

However, though he had wanted to avoid destruction within the city of Rome, which would damage his reputation, he had ordered troops to Italy to bring Clement under his control.

[16][9][17][18] Cumulatively, these actions changed the complexion of the Catholic Church, steering it away from Renaissance freethought personified by the Medici Popes, toward the religious orthodoxy exemplified by the Counter-Reformation.

After Clement's death in 1534, under the influence of Charles and later his son King Philip II of Spain (1556–1598), the Inquisition became pervasive, and the humanism encouraged by Renaissance culture came to be viewed as contrary to the teachings of the Church.

Clement opposed this, believing that monarchs shouldn't dictate Church policy; and also fearing a revival of conciliarism, which had exacerbated the Western Schism during the 14th–15th centuries, and deposed numerous Popes.

After the sack, Clement acceded to Charles' wishes, agreeing to call a Church Council and naming the city of Trent, Italy as its site.