Fort St Angelo was the major fortification used by the Knights on the island. Even after Fort St Elmo, and then Valletta, were built, Fort St Angelo remained a centrepiece of their defensive systems. Juan de Homedes was primarily interested in the building up of the sea power of the order, and saw the Malta defenses as secondary to this aim. The Galleys could be sheltered in the 'Canal' - the stretch of water between St Angelo and Birgu. In case of serious attack, the Galleys could be sent to Sicily or Tripoli (until Tripoli fell) for safety.

Over time, the fortifications around St Angelo grew: in 1551 St Angelo already existed. Between 1551 and 1565 the fortifications around Birgu itself were significantly strengthened; Senglea (on the site of L'Isla) was added with Fort St Michael to protect it. A ring of fortifications at the head of Galley Creek was started, to enable Senglea and Birgu to re-inforce each other. St Elmo was built.

After the siege of 1565, the Knights went into overdrive - terrified that the Turks might return the following year to the ruined St Angelo and St Elmo, they kept an army of 8,000 soldiers and used many civilians as they rebuilt the fortification. They were greatly assisted, at last, by the Princes of Europe who realised how close the Turks had come to gaining a powerful base in the western Mediterranean from which they could wreak havoc on Christendom's shipping, and launch an invasion of Sicily.

The Turks did not return - after the sea battle of Lepanto (at which the knights fought) they no longer had the ability to do. Italy was invaded from Malta and North Africa - but not until 1943, and then by Allied troops.