Missy's parents, Cyrus and Monica, are played by Jordan Peele and Chelsea Peretti, who are married in real life.
Nick and Andrew are based off of the show's co-creators Nick Kroll and Andrew Goldberg, and much of the show's content reflects real events from their life. The other cast members also often served as inspiration for their respective characters. For example, Jenny Slate used to be quite small and wore overalls, like her character Missy, until one senior student came up to her and yelled to her: "Why do you look like a baby?"
Tyler refers to the Shame Wizard as "the guy with the Harry Potter accent." The Shame Wizard is voiced by David Thewlis who played Remus Lupin in the Harry Potter films.
Nick Kroll voices up to twelve characters, including Nick Birch, Maurice the Hormone Monster, and Coach Steve.
During the sixth episode when Andrew and Nick visit the city, there's a billboard for the show "Oh, Hello on Broadway" which Nick Kroll and John Mulaney wrote and starred in together.