Pope Innocent VIII dies. Rodrigo Borgia wins election as Pope Alexander VI by bribing enough of the cardinals to vote for him in conclave. Alexander "packs" the College of Cardinals with 13 new members, including his son Cesare. He then tries to contract an alliance with the powerful family of Cardinal Ascanio Sforza, one of his two original rivals for the Papacy. That alliance, ever fragile, breaks after Alexander's other rival, Cardinal Giuliano della Rovere (the future Pope Julius II), contracts his own alliance with the King of France for an invasion of Italy.

Having survived the French invasion with his Papacy intact (just barely), Alexander VI containues to advance his agenda. But the Sforza family continues to thwart him, leading him to make physical war upon them. Nor has Cardinal Giuliano della Rovere given up trying to rid the Vatican of Alexander. Having failed to depose the Pope legally, Cardinal della Rovere plots to assassinate him.

Alexander VI survives Cardinal Giuliano della Rovere's assassination attempt, because his daughter Lucrezia knows how to treat catarella poisoning. Alexander's war with the Sforza family continues and escalates. Alexander now plots to turn the Papacy into an explicitly hereditary office.