After a two-year break, Mc Adams starred in two limited release films in 2008; the film noir Married Life and the road trip drama The Lucky Ones.

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Todd Mc Carthy of Variety criticized her break from the big screen but felt that, despite a performance of "tender feeling", "her natural vivaciousness and spontaneity are straightjacketed" by the film noir format.

Afterwards, Mc Adams starred with Tim Robbins and Michael Peña in the road trip comedy-drama The Lucky Ones, a story about three Iraq War soldiers on a brief road trip back in the United States.

For her performance in Spotlight, she was nominated for the Academy Award for Best Supporting Actress.

In 2016, she starred as Christine Palmer in the Marvel Cinematic Universe superhero film Doctor Strange.

while Roger Ebert of the Chicago Sun-Times asserted that "she brings more presence and credibility to her role than is really expected; she acts without betraying the slightest awareness that she's inside a genre.

Her performance qualifies her for heavy-duty roles." In late 2005, Mc Adams starred with Sarah Jessica Parker and Diane Keaton in the seasonal family comedy-drama The Family Stone, which gave Mc Adams an opportunity to play a dishevelled and sardonic sister, rather than the usual "obvious" girlfriend or wife roles.

In 2010, Mc Adams appeared in her first star vehicle, the comedy Morning Glory.

In 2015, her highest profile roles were in the second season of the HBO crime drama True Detective, and as journalist Sacha Pfeiffer in the drama Spotlight.

Tina Fey, who co‑starred in the film and wrote the screenplay, has credited Mc Adams with teaching her how to act in front of a camera rather than an audience: "She's a film actor. And so I kind of learned that lesson from watching her." Later in 2004, Mc Adams starred opposite fellow Canadian Ryan Gosling in the romantic drama The Notebook, based on Nicholas Sparks' novel of the same name.

She played Allie Hamilton, a wealthy southern belle who has a forbidden love affair with Gosling's poor labourer, Noah Calhoun.

In 2005, she starred in the romantic comedy Wedding Crashers, the psychological thriller Red Eye, and the comedy-drama The Family Stone.