John Cameron Mitchell directed the movie Rabbit Hole with Nicole Kidman (nominated for Best Actress at the Oscars for that role) for which he was nominated at the Independent Spirit Award, in the Best Director category. He wrote, directed and starred in the movie Hedwig and the Angry Inch (2001), for which he received the Best Director Award and the Audience Award at the Sundance Film Festival. He has also been nominated at the Oscars in the Best Actor category. He is the executive producer of the documentary Tarnation by Jonathan Caouette (2004). His film Shortbus was released in 2006. On Broadway, the staging of Hedwig and the Angry Inch received the Tony Award for Best Revival of a Musical Comedy (2014).
In 2015, John was awarded a Special Tony Award for his return to the lead role. His film How to Talk to Girls at Parties was presented for the first time Out of Competition at the Cannes Film Festival in 2017.