In 1557, upon the death of Grand Master Claude de la Sengle, the Knights, mindful of the attack that was sure to come, elected Valette to be Grand Master.
He fought and successfully repulsed the Turks at the Great Siege of Malta in 1565, in which the vastly outnumbered Christians held out for over 3 months against an Ottoman force containing no less than 30,000 soldiers, including the Janissaries, as well as the Sultan's fleet of some 193 ships.