After seven years of moving from place to place in Europe, the Knights were re-established on Malta in 1530 by the order of Pope Clement VIII and Emperor Charles V of Austria, with the consent of their feudal landlord the King of Sicily. Their annual fee for the island was a single Maltese falcon, which they had to give annually on All Souls Day to the Viceroy of Sicily, who acted as the King's representative. Here the once-again re-named Knights of Malta continued their actions against piracy, their fleet targeting the Barbary pirates.
Although they had only a small number of ships, they nevertheless quickly drew the ire of the Ottomanss who were less than happy to see the order re-established. Accordingly they assembled another massive army in order to dislodge the Knights from Malta, and in 1565 invaded. At first the battle looked to be a repeat of the one on Rhodes. Most of the cities was destroyed and about half the Knights died in battle. But things changed dramatically when a relief force arrived from Spain. In the ensuing retreat the Ottomans lost some 30,000 men, enough to secure the island for a time. The siege is vividly portrayed in the frescoes of Matteo Perez d'Aleccio in the Hall of St Michael and St George, also known as the Throne Room, in the Grandmaster's Palace, Valletta. Four of the original modellos, painted in oils by Perez d'Aleccio himself between 1576 and 1581, can be found in the Cube Room of the Queen's House, Greenwich, London. After the siege a new city had to be built -- the present city of Valletta, so named in memory of its valiant grand master La Valette who had sustained this siege.
In 1571 the growing Ottoman fleet decided to give challenge once again, but this time were met at sea by a huge and very modern Spanish fleet under the command of Don Juan de Austria (son of Emperor Charles V). The Ottomans were outgunned, outmanuvered and outrun, and by the end of the day almost the entirety of their fleet was destroyed or captured in what is now known as the Battle of Lepanto. The battle, however, had little political impact for the Ottomans quickly rebuilt their fleet.
Following the victory at Lepanto the Knights continued to attack pirates, and their base became a centre for slave trading, selling captured Africans and Turks and conversely freeing Christian slaves. Malta remained a slave market until well into the eighteenth century. It required a thousand slaves to equip merely the galleys of the order.