Shadix was born William Glenn Shadix in Bessemer, Alabama. He attended Birmingham-Southern College for two years, studying with absurdist playwright-director Arnold Powell. He lived in New York City prior to moving to Hollywood in the late 1970s. He got his breakthrough film role in Beetlejuice while doing a stage play, portraying Gertrude Stein. According to Shadix, it was the play that his agent warned him against doing, since it was a role that seemed too risky. But the actor went on instinct and played the role. As fate would have it, Tim Burton was one of the people sitting in the audience that night. Shadix became personal friends with Burton while making Beetlejuice, and the two would go on to make two more films together: 1993's The Nightmare Before Christmas and the 2001 remake of Planet of the Apes.
In 2005, Shadix was cast as the Brain and Monsieur Mallah in season five of the Teen Titans animated series. Other voice work done by Shadix includes the aforementioned Nightmare, and episodes of Jackie Chan Adventures and Justice League Unlimited. He reprised his Nightmare Before Christmas role in the sequel, Oogie’s Revenge, and the Square-Enix video game Kingdom Hearts II.
His television work included the HBO drama Carnivàle, the NBC television comedy Seinfeld, in which he played Jerry's landlord, and playing the roles of giant brothers Typhoon and Typhon in "Hercules: The Legendary Journeys".
On stage, Shadix was set to begin rehearsals for History Boys, the award winning Broadway play by Alan Bennett. It would have been Shadix's first time back in Birmingham Theatre since 1973 when he appeared in Boys in the Band at the Birmingham Festival Theatre.
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