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He made his screen debut in an episode of CBS Summer Playhouse (1989), followed by minor film roles.
He was part of the original cast of This Is Our Youth (1996), for which he was nominated for an Independent Spirit Award.
Following were his roles in 13 Going on 30 (2004), Eternal Sunshine of the Spotless Mind (2004), Zodiac (2007), and What Doesn't Kill You (2008).
In 2010, he starred in the psychological thriller Shutter Island and the comedy-drama The Kids Are All Right.
"We had a great time together, and I think we would, but then Ben [Affleck] came on the scene and that was the end of that," Ruffalo said smiling.