Lorenzo di Piero de' Medici: As with the previous season, Lorenzo showed great political skill in navigating the conflict with Rome and Riario. He also was skillful in placing his son and nephew in a position to eventually become two well-known Popes. However, he neglected the family bank and after his reign the bank went bankrupt. The Medicis also became unpopular after his reign and were ousted from the city for a period. He was also shown as an early patron of Leonardo da Vinci and Michelangelo. The politics of the time also was shown as possibly influencing Niccolò Machiavelli in his late writings.
Pope Sixtus IV: He supported the conspiracy against the Medici and became involved in a conflict with the Medici. Ultimately, this conflict taught the Medicis they needed to have greater influence in the Vatican, leading to Lorenzo placing his son and nephew in Rome.
Girolamo Riario: Rival to the Medicis who supported the Pazzi conspiracy and became a leader in the war against them. He not only failed but lost his life due to the increasing unpopular reign of his leadership.
Girolamo Savonarola: A friar that created difficulties for the Medici. He led religious revivals and, although he was initially supported by the Medici, he also preached for popular government and preached against Medici corruption and dictatorial rule.
Clarice Orsini: While most of the Medici family were humanists and were great patrons of the art, she was more religious and while she supported her family she also became concerned with its corruption. She ultimately dies in an unexpected death perhaps strained by the stress of the family's style of rule.