Discord/Knifehead: Both manage to break the main character(s). (Discord turns the Mane 6 into shadows of themselves; Knifehead kills Yancy Becket and puts Gipsy Danger out of commission leading to Raleigh retiring).
 
Sombra/Slattern: Powerful enemies who are not to be taken lightly.
 
Chrysalis/Otachi: Dangerous uber bitches who give the heroes a really hard time as well as defeating powerful figureheads. (Chrysalis for Celestia and Otachi for Crimson Typhoon.)
 
Diamond Tiara and Silver Spoon/Scunner and Raiju: Antagonists who work together.
 
Gilda/Mutavore: Female characters who only show up once for a short time.
 
Diamond Dogs (Fido featured)/Leatherback: Brutish thugs who rely more on their brawns as opposed to their brains.