The Swiss Guard, founded January 22, 1506, is the elite bodyguard for the Pope. It protected Pope Clement VII on May 6, 1527 during the Sack of Rome by 20,000 German and Spanish mercenaries commanded by the Duc de Bourbon. When the Habsburg Emperor was unable to pay this army, the mercenaries' contract allowed for looting. Bourbn decided to attack Rome, full of riches and almost defenseless. The Swiss Guard consisted of 189 men, lead by their Captain, Kaspar Roist. The unit lost 142 men including Roist while killing 900 mercenaries. The remaining Swiss Guard evacuated Pope Clement VII to Castel Sant' Angelo using the "Passetto", a secret corridor constructed under Pope Alexander VI along the top of a wall between the Vatican and the Castel.

Leaving the Hundred Years War, English mercenary Sir John Hawkwood makes a name for himself in 14th-century Italy by serving a variety of sponsors, including Pope Gregory XI in the War of the Eight Saints. This medieval English knight with his army, the White Company, becomes the scourge of Italy, often without striking a single blow.