"While the Renoir Crown rules the the Canopy Kingdom, the Medici rule its sizable underworld. On the surface, the wealthy Medici family is noble and generous, but beneath this facade lurks the truth: most everyone of power in New Meridian is being manipulated, coerced or directly controlled by the Medici crime family."
Filia is related to the Mafia by blood, according to Marie. Hints in the game suggest she is Lorenzo Medici's granddaughter, though she could also simply be the daughter of another Mafia member. Though Alex Ahad has stated that she is indeed Lorenzo's granddaughter via a Stalty Cupcakes stream, this information is still ambiguous until placed officially into the game.
Peacock and Marie's lives were changed by the Mafia. They are behind the slave traders of Rommelgrad who captured and mutilated Patricia. Marie would later find the Skull Heart, with which she wished to destroy the traders, thus becoming a Skullgirl.
Parasoul listed the Mafia as one of her dislikes. She is working hard to bring them to justice. As she gets ready to fight Cerebella, she says she has a message for her boss.
Ms. Fortune also listed the Mafia as one of her dislikes. Their hitwoman Black Dahlia sliced her and The Fishbone Gang into many pieces. But since she swallowed the Life Gem, Ms. Fortune didn't die and is now working to avenge her gang. When she defeats Cerebella she says her bosses are next.
Squigly being a distant victim of the Medici mafia, she was reanimated by her mother Selene Contiello when the latter became the next skullgirl after a disguised Double gave the heart to her as a birthday gift and alerted the crime family of her latest acquisition. After Lorenzo Medici defamed the Contiello's by stitching the mouths of their dead shut Squigly found herself alive again with the new skullgirl gunning for the Medici's.
Big Band having been a straight laced cop in the grungy criminal underworld of meridian city, Ben Birdland had been brutally betrayed and beaten within an inch of his life by crooked cops on the Medici's Payroll. ASG Labs eventually found him and remade him into the Cyborg soldier Big Band, now a senior officer he acts as the overseer and father figure to the younger Anti-Skullgirl requites.
- The Medicis are descendants of the original inhabitant of the land prior to it being conquered by the Canopy Kingdom. This is part of the reason they are the nemeses of the Renoirs.
- Although Filia is part of the Medici bloodline, Riccardo does not recognize her, despite working for the family. One theory is that Riccardo did not recognize her due to the fact Samson had changed Filia's hair color (which used to be blonde).
- The portrait depicting Lorenzo shows him in his youth, prior to his hair turning grey, whilst the portrait of Vitale depicts him older than he appears in the present. The ages of the family members are questionable, due to their use of the Life Gem.
- The name Medici is likely a reference to the Medici noble family in Renaissance Italy. Sometimes referred to as the "original crime family", the Medici family's dramatic impact on religion, politics and art in Europe is often described as a defining feature of the Renaissance era.