In Assassin's Creed II, Rodrigo Borgia is Ezio Auditore's main political enemy.
Rodrigo Borgia appears as the Grand Master of the Italian Templars and uses political power to pursue the Apple of Eden. Historically, Rodrigo became Pope Alexander VI in 1492, and the game incorporates that real identity into its fictional conflict between Assassins and Templars.
Cesare Borgia, Rodrigo's son, is a major antagonist in Assassin's Creed: Brotherhood rather than the principal villain of Assassin's Creed II. The game's climax takes Ezio to the Vatican in 1499, where he confronts Rodrigo over the Papal Staff and the Apple of Eden.