After the conquest of Constantinople by the Crusaders in 1204, at the instigation of the Republic of Venice and the consequent weakening of the Byzantine Empire, the Venetians and the Genoese competed for supremacy on the island of Kos , then named Lango. The Genoese succeeded for some time to add Lango to the other major islands (Metelino and Scio) they already had near the coast of Asia Minor. The Venetians conquered the island of Kos, but in 1314 the Genoese corsair Vignolo of Vignoli, lord of the island, appealed to the Knights of St. John. After a brief occupation, the Venetians sold the island Lango to the Knights Hospitallers of St. John, also known as Knights of Rhodes , where the headquarters of the Order was established since 1306.
Until 1336, the situation remained contentious and it is possible that the island was taken over by the Venetians, or even whether temporarily returned to the Byzantine Empire. From 1337, the Knights of St. John held firmly Kos: The Order of St. John on the island had its own governors who were appointed by the Council of the Knights of Rhodes ; they closely controlled the island and its inhabitants.
The fourteenth century saw the first attacks by the Turks, the Hospitallers managed to repulse the attacks in 1457 and 1477, mainly because of the power they had built fortifications on the island. These include the Castle Neratzia at the entrance of the port of Kos town , the castle of Antimahia the center of the island, which was unsuccessfully attacked in 1457, Castle Palaio Pyli and Castle Kefalos . Today, repairs of the the damages done by the Turkish attacks on the two most important castles, and Neratzia than that of Antimahia are clearly visible.
The island of Kos was not taken by the Ottomans, but the Order of St. John had to give it to them in 1523 after the fall of Rhodes . The Knights had ruled the island for about two centuries.