- Disabled Character, Disabled Actor: Alice Wong plays a fictionalized version of herself, who is also a disability activist with spinal muscular atrophy.
- In Memoriam: "It's Almost Over" is dedicated to Willie Garson.
- Irony as She Is Cast: The male and female Hitlers from the Hate Division are voiced by Jewish born Nick Kroll.
- Queer Character, Queer Actor:
- Sabrina Jalees and Ariana DeBose, two lesbians, play Nadja and Danielle, a young lesbian couple.
- Miley Cyrus, who is queer, plays Van, a Logic Rock who hooks up with Emmy in Season 2.
- Real Song Theme Tune: The theme song is Janelle Monáe's 2018 single "Make Me Feel."
- You Sound Familiar: The recurring cast features Ali Wong, Hugh Jackman, and later Jason Mantzoukas, all of whom originally appeared in Big Mouth. However, they portray different characters than they did in that show.
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