When the Hospitallers retreated to Cyprus, the island was ruled by the titular king of Jerusalem, Henry II of Cyprus. He was less than pleased that an organization as powerful as the Order could compete with him for the sovereignty of his small island and likely set Guillaume de Villaret on the path to conquer the island of Rhodes.

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.