Lange performed his first stand-up comedy routine at 19 years of age. He took up work as a longshoreman to help support his family following the death of his quadriplegic father. In 1995, Lange starred in the first season of MADtv before leaving halfway through the second due to cocaine abuse and his subsequent arrest. After a period of rehabilitation, Lange featured in Dirty Work with Norm Macdonald, who brought Lange into the second season of his sitcom, The Norm Show. In 2001, Lange joined The Howard Stern Show until December 2009 when a suicide attempt in January 2010 led to an eight-month stay in a psychiatric ward. In 2011, Lange returned to radio with Nick DiPaolo to co-host The Nick & Artie Show. In January 2013, it was renamed The Artie Lange Show after DiPaolo's departure.
Lange has released two recordings of comedy performances–It's the Whiskey Talkin' and Jack and Coke.
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