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Burton made his directorial debut with the comedy film Pee-wee's Big Adventure (1985). He gained wider prominence for directing Beetlejuice (1988) and Edward Scissorhands (1990), as well as producing The Nightmare Before Christmas (1993), which was based on a poem he wrote. He had directed films spanning a variety of genres such as animation, biopic, drama, fantasy, musical, science fiction, superhero, and supernatural horror; these include Batman (1989), Batman Returns (1992), Ed Wood (1994), Mars Attacks! (1996), Sleepy Hollow (1999), Planet of the Apes (2001), Big Fish (2003), Charlie and the Chocolate Factory (2005), Corpse Bride (2005), Sweeney Todd: The Demon Barber of Fleet Street (2007), Alice in Wonderland (2010), Dark Shadows (2012), Frankenweenie (2012), Big Eyes (2014), Dumbo (2019), and Beetlejuice Beetlejuice (2024).

Burton has directed several episodes of the Netflix series Wednesday (2022–present), for which he was nominated for the Primetime Emmy Award for Outstanding Directing for a Comedy Series. He frequently collaborates with musician Danny Elfman, who has scored all but three of his films. He has also published several books, including The Melancholy Death of Oyster Boy & Other Stories (1997).