Assassin's Creed: Brotherhood - 15th Century, 2012
In Brotherhood, we learn what happens to Ezio after leaving the vault. Although confused by his conversation with Minerva, Ezio has more immediate concerns: his villa has been overrun by Templars and his family are in danger. The villa is besieged by Cesare Borgia, son of Rodrigo - now Pope Alexander VI - who kills Ezio's uncle, Mario and makes off with the Apple of Eden. Ezio and the remnants of his family escape to Rome, where the remainder of Brotherhood takes place. Ezio promises to rally together a brotherhood of assassins, and end the Borgia's regime for once and all.
Over the next four years, Ezio burns down all the Borgia towers in Rome, crippling the influence the family has over the city. Meanwhile, Cesare - a man campaigning to be King of Italy, a man desperate for power - asks his father for the Apple. Taken back by his son's unquenchable thirst for power, Rodrigo attempts to poison his son, but Cesare is able to turn the tables on his father, who ends up dead instead.
Lurking in the shadows, Ezio sees the entirety of this, learning the location of the Apple in the process. Recovering it from St. Peter's Basilica, Ezio then uses the Apple (which holds great power) to overwhelm Cesare's forces, thwarting his campaign for the throne, and decimating the respect of all his supporters. Cesare is soon arrested by Pope Julius II's Papal Army, and forced to leave Rome.
Years later, with his family safe and Rome left in peace, Ezio uses the Apple one more time to check on Cesare. It's a good job too, because he had escaped prison and laid siege to a small city in Navarre, Spain. Finding him on the crumbling battlements of an old castle, Ezio does battle with Cesare for the last time. Left in a vulnerable position, Cesare claims that he can't be killed by the hand of a man, so Ezio drops him off the battlement and let's fate do it's job. Ezio has onbe last task: hiding the Apple somewhere it'll be safe for a very long time; underneath Santa Maria in Aracoeli.
Desmond's DNA 'activates' the apple, and something possesses him. With an invisible puppeteer controlling his body, Desmond plunges a knife into poor Lucy, who is herself paralysed, stuck in some sort of time void.
One of the last things we hear in the game, is Minerva saying "Awaken the sixth!" - but what this might mean is anybody's guess.