Alternately neglected and abused by her cruel husband, Lucrezia has an affair with Paolo, a handsome stable boy; Cesare strikes a bargain with Machiavelli: deny French troops passage across his masters' lands in exchange for suppression of Savonarola, a fiery preacher of anti-Medici sermons; in love with baroness Ursula, Cesare takes drastic action to get rid of her husband.

Della Rovere reaches France and strikes a bargain with its ruler to invade Italy and install him on the Papal throne in exchange for control of Naples; Rodrigo attempts to thwart the invasion through an alliance by marrying his youngest son Joffre to Princess Sancia of Naples (guest star Emmannuelle Chriqui), but Juan nearly sabotages the plan by seducing his prospective sister-in-law.

Alexander is convinced that a lightning strike on St. Peter's Basilica during mass was a sign of God's disapproval; Cesare tries to prove his worth as a military commander; the Pope pressures the reluctant Lucrezia to enter another political marriage.

Juan returns to Rome trying to spin his combat injury as proof of his valor, but Cesare exposes his brother's ignoble behavior; Lucrezia takes a lover in her intended husband's younger brother; Della Rovere has recruited an angel-faced young friar as his suicide assassin, and the young man advances their agenda with a bold move against the Pope's food taster.