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After garnering attention in television productions Made in Britain (1982) and Meantime (1983), Roth was nominated for the BAFTA Award for Most Promising Newcomer in his theatrical film debut The Hit (1984). He gained further recognition for his roles in films, including The Cook, the Thief, His Wife & Her Lover (1989), Vincent & Theo and Rosencrantz & Guildenstern Are Dead (both 1990). Roth has collaborated with Quentin Tarantino on several films, including Reservoir Dogs (1992), Pulp Fiction (1994), Four Rooms (1995) and The Hateful Eight (2015). Other film credits include The Legend of 1900 (1998), Planet of the Apes (2001), Funny Games (2007), Selma (2014), Luce (2019), and Bergman Island (2021).

Roth made his directorial debut with~ The War Zone (1999). He played Cal Lightman in the Fox series Lie to Me (2009–2011), Jim Worth / Jack Devlin in the Sky Atlantic series Tin Star (2017–2020), and Emil Blonsky / Abomination in the Marvel Cinematic Universe, including the films The Incredible Hulk (2008), Shang-Chi and the Legend of the Ten Rings (2021), and the Disney+ series She-Hulk: Attorney at Law (2022).