| Having at last dealt with the French threat, Pope Alexander VI is free to focus on two enemies who have recently emerged as far more dangerous than he had realized: the Dominican Friar Savonarola whose firebrand preaching has upset the Florentine status quo and attracted the Pope's attention and his former ally-turned-French-collaborator Caterina Sforza, who's retired to her castle at Forli that is now protected by a worrisome amount of French cannons. Cesare is sent to the powerful countess bearing news of the papal edict that demands her immediate insubordination and Rodrigo himself, along with Ascanio Sforza, rides to Florence to witness one of Savonarola's sermons for themselves.|
Meanwhile, back in Rome the three ladies of the Pope's heart and confidence, Giulia Farnese, Vanozza Cattaneo and Lucrezia Borgia start planning how to better approach their targets: the cardinals in the Curia who have been indulgent in secular luxuries at the expense of the papal treasury and the people of Rome. The three women visit a decrepit brothel that is currently playing host to two cardinals and offer the madame a tantalizing offer: to restore the brothel to cleanliness and comfort if she agrees to provide information on the cardinals who frequent it.
Cesare with Micheletto by his side arrives at Forli and learns that the town is actually his head henchman's birthplace. There, Micheletto pays a visit to his mother who runs a tavern and Cesare is surprised to learn that Micheletto's loving parent is oblivious to her son's employment as the cardinal's enforcer, believing instead that he is a medicine student in Rome, and also that Micheletto committed patricide for a variety of obscure reasons. Micheletto is reunited with a childhood friend, whom he meets later at night in a cemetery, next to his father's grave, and is revealed to be having a sexual relationship with the man who is soon to be married and is openly judgmental of Micheletto's real occupation and lifestyle. The two men part ways soon after, with Micheletto clearly in anger over his partner's denial to break off his engagement and follow him to Rome.
Cesare arrives at Caterina Sforza's castle and meets her son, Benito, a sweet but rather submissive young boy. The Sforza matron is clearly procrastinating in answering the Pope's demand that she come to Rome willingly and declare herself a vassal to the papacy or be forced to do so and openly flirts with Cesare before tricking him into entering her chambers and seducing him. Cesare and Caterina seem to be enjoying the mostly physical relationship as well as the intellectual, political back-and-forth, especially when Sforza reveals herself to be aware of the cardinal's cannon rouse that made the French leave Rome unscathed for a second time.
In Florence, Rodrigo enters the city's cathedral in disguise to hear Savonarola speak mere seconds before Della Rovere arrives also to get the Friar's approval on the Pope's assassination. Astounded by the Friar's passion, Rodrigo visits the Medici who are barricaded inside their palace in fear of Savonarola's zealots. The Pope is informed that the Church's accounts with the Medici Bank are, just like the Borgia family fortune that is deposited in the same institution, jeopardized due to the instability that Savonarola's anti-luxury sermons are provoking. Rodrigo is worried for his money and suggests that they be moved to Rome for protection but is warned by his Florentine allies not to attempt something of the sort as Savonarola's spies are everywhere. Rodrigo ponders the question of how best to neutralize the Friar and is informed that neither money nor ecclesiastical office will silence Savonarola who fancies himself God's voice and will only be dealt with by severe measures.
Cesare at Forli is getting bored of the cat-and-mouse game with Caterina Sforza and realizes that no matter what he'll do, the Lady will give him a negative answer. He declares a deadline for the Sforza countess to give him her answer so that he will be able to go on with his business and plan his next move but the Lady doesn't seem ready to let him leave just yet and the two adversaries fornicate once again, just before Giovanni Sforza arrives to provide support for his cousin. Cold and callous about his betrayal to the Borgia papacy and Cesare's beloved sister, Lucrezia, Giovanni Sforza is the unfortunate victim of Cesare's rage when Caterina Sforza understandably and expectedly refuses to grant the Pope's favour and swear allegiance to him. Stabbed countless times through the neck and the abdomen, Giovanni dies and Cesare escapes Forli with Micheletto just in time. Cesare proposes that they follow different paths back to Rome in order to avoid getting followed by potential Sforza agents and hands Micheletto the crime weapon -a dinner knife- that he intends to present to Lucrezia.
In Rome, Della Rovere having been blessed by Savonarola as God's own instrument to take Rodrigo Borgia's life starts recruiting men from the Dominican order to train them as assassins. Nobody is willing to step up and lose his life as a taster for the Pope who is unavoidably to be poisoned and perish for the plan to come to fruition but for a young, angelic boy who offers himself up to be sacrificed. Saint Peter's, where Pope Alexander VI is performing the Eucharist, is soon struck by a bolt of lightning and the old roof collapses turning the commune into a chaotic flee. Amidst the chaos, the only valiant man is the Pope himself who attemps to save the children of the choir but is unsuccessful, endangering his own life. After the rubble and the dust has settled, Rodrigo, thinking the natural event was a sign of God's severe disapproval of his actions, vows to atone for his sins by fasting and praying for as long as he needs to.