In 1979, Willem Dafoe was given a small role in Michael Cimino's Heaven's Gate from which he was fired. His first feature role came shortly after in Kathryn Bigelow's The Loveless. From there, he went on to perform in over 70 films - in Hollywood (Spider-Man, The English Patient, Finding Nemo, Once Upon A Time In Mexico, Clear And Present Danger, White Sands, Mississippi Burning, Streets Of Fire, American Dreamz) and in independent cinema in the U.S. (The Clearing, Animal Factory, The Boondock Saints, American Psycho) and abroad (Theo Angelopoulos' The Dust Of Time, Yim Ho's Pavillion Of Women, Yurek Bogayevicz's Edges Of The Lord, Wim Wenders' Faraway, So Close, Nobuhiro Suwa's segment of Paris Je t'aime, Brian Gilbert's Tom & Viv, Christian Carion's Farewell, Mr. Bean's Holiday and The Spierig Brothers' Daybreakers).

He has chosen projects for diversity of roles and opportunities to work with strong directors. He has worked in the films of Wes Anderson (The Life Aquatic, The Fantastic Mr. Fox), Martin Scorsese (The Aviator, The Last Temptation Of Christ), Spike Lee (Inside Man), Julian Schnabel (Miral, Basquiat), Paul Schrader (Auto Focus, Affliction, Light Sleeper, The Walker, Adam Resurrected), David Cronenberg (Existenz), Abel Ferrara (Go Go Tales, New Rose Hotel), David Lynch (Wild At Heart), William Friedkin (To Live And Die In LA), Werner Herzog (My Son My Son What Have Ye Done), Oliver Stone (Born On The Fourth Of July, Platoon), Giada Colagrande (A Woman and Before It Had A Name) and Lars von Trier (Antichrist and Manderlay).

He was nominated twice for the Academy Award (Platoon and Shadow Of The Vampire) and once for the Golden Globe. Among other nominations and awards, he received an LA Film Critics Award and an Independent Spirit Award.