That same year, he starred in P.S., which received only a limited theatrical release. Grace won the National Board of Review's 2004 award for Breakthrough Performance Actor for his work in In Good Company and P.S. On January 15, 2005, Grace hosted Saturday Night Live. In 2007, Grace portrayed Eddie Brock/ Venom in Spider-Man 3, directed by Sam Raimi. In 2009, Grace became the subject of a recurring column on the entertainment/pop culture site Videogum, entitled "What's Up With Topher Grace?" Grace himself was a fan of the comics and read the Venom stories as a child. In 2010, Grace appeared in the ensemble comedy Valentine's Day and played the character of Edwin in Predators. In 2011, Grace appeared in the 1980s retro comedy Take Me Home Tonight. He co-wrote the script and co-produced the film. Grace also starred opposite Richard Gere in the spy thriller The Double.
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In 2012, Grace starred alongside Mary Elizabeth Winstead and Matthew Gray Gubler in the social film The Beauty Inside, which won a Daytime Emmy Award for Outstanding New Approach to an Original Daytime Program or Series in 2013. The film was directed by Drake Doremus and written by Richard Greenberg. In 2014, Grace starred in the indie thriller The Calling, alongside Susan Sarandon, and appeared in Christopher Nolan's sci-fi adventure Interstellar, in a supporting role. In October 2013, Grace joined HBO comedy pilot People in New Jersey with Sarah Silverman, but in January 2014, the pilot was passed on.