Following the Fall of Acre in 1291, the Order had moved its base to Limassol in Cyprus. Their position in Cyprus was precarious; their limited income made them dependent on donations from Western Europe and involved them in quarrels with King Henry II of Cyprus, while the loss of Acre and the Holy Land led to widespread questioning on the purpose of the monastic orders, and proposals to confiscate their possessions. According to Gérard de Monréal, as soon as he was elected as Grand Master of the Knights Hospitaller in 1305, Foulques de Villaret planned the conquest of Rhodes, which would ensure him a liberty of action that he could not have as long as the Order remained on Cyprus, and would provide a new base for war against the Turks.

Rhodes was an attractive target: a fertile island, it was strategically located off the southwestern coast of Asia Minor, astride the trade routes to either Constantinople or Alexandria and the Levant. The island was a Byzantine possession, but the increasingly feeble Empire was evidently unable to protect its insular possessions, as demonstrated by the seizure of Chios in 1304 by the Genoese Benedetto Zaccaria, who secured recognition of his possession from Emperor Andronikos II Palaiologos (r. 1282–1328), and the competing activities of the Genoese and Venetians in the area of the Dodecanese. 

The Hospitaller conquest of Rhodes took place in 1306–1310. The Knights Hospitaller, led by Grand Master Foulques de Villaret, landed on the island in summer 1306 and quickly conquered most of it except for the city of Rhodes, which remained in Byzantine hands. Emperor Andronikos II Palaiologos sent reinforcements, which allowed the city to repel the initial Hospitaller attacks, and persevere until it was captured on 15 August 1310. The Hospitallers transferred their base to the island, which became the centre of their activities until it was conquered by the Ottoman Empire in 1522.