McAdams played the titular role in the film The Hot Chick alongside Rob Schneider, but her career really took off when she starred as Regina George, the "queen-bee" in 2004's Mean Girls. McAdams was told to partly model the character of Regina George after Alec Baldwin's performance in Glengarry Glen Ross (1992). She was much older than the character she played. McAdams had previously appeared in the Canadian television series Slings and Arrows, alongside Paul Gross. She played a main role in the first season, but due to her rising stardom was written out of the second season, appearing in only the first episode. She followed Mean Girls with the film adaptation of Nicholas Sparks' novel The Notebook, alongside Ryan Gosling, with whom she would later begin an off-screen romance. In 2005, she played Owen Wilson's love interest in Wedding Crashers and then starred in the suspense thriller Red Eye as Lisa Reisert, where she played a young woman held captive aboard a red-eye flight by criminal-for-hire and assassin Jackson Rippner (Cillian Murphy). Rachel was in The Family Stone where she starred in an ensemble cast alongside Diane Keaton, Craig T. Nelson, Sarah Jessica Parker, Dermot Mulroney, Luke Wilson, Brian J. White and Claire Danes. McAdams auditioned for the role of Sue Storm in Fantastic Four, and only just lost the part to Jessica Alba.

McAdam's career slowed down in 2006. She was originally signed on as the female lead in The Last Kiss but had to drop out due to scheduling conflicts, and the role was given to Jacinda Barrett. She decided to take a year off from acting, to spend time with friends and family. McAdams then signed on to star in the drama Married Life with Pierce Brosnan and Patricia Clarkson. She turned down the role of bond girl "Vesper Lynd" in the James Bond film Casino Royale. McAdams was also in-talks to star in Iron Man and The Dark Knight, but she declined both roles. She stated in an interview in May 2006 that she did not want to star in a big-budget action film because she wanted to pursue other projects.

Despite having appeared nude in The Notebook and My Name is Tonino McAdams opted out of a cover shoot for Vanity Fair—in which she was to appear alongside two other young Hollywood actresses, Scarlett Johansson and Keira Knightley—upon finding out it was to be nude. Tom Ford, artistic director for the cover, instead appeared with them. When McAdams appeared on set and discovered it was nude, she politely declined, according to Knightley. McAdams will been seen next in the upcoming political thriller State of Play alongside Academy Award winners Ben Affleck, Russell Crowe and Helen Mirren. Production wrapped in April 2008 and the film will be released theatrically April 17, 2009. In October 2008, McAdams was announced to be starring in Guy Ritchie's new film Sherlock Holmes - based on Sir Arthur Conan Doyle's classic stories. McAdams will play the role of Irene Adler alongside Robert Downey Jr and Jude Law. Filming began in October for release a year later. Also, she will be starring in David Fincher's next crime movie Ness alongside Matt Damon and Casey Affleck. She also signed on for Morning glory with Harrison Ford.

• Morning Glory (2010) (pre-production)
• Sherlock Holmes (2009) (filming) .... Irene Adler
• State of Play (2009) (completed) .... Della Frye
• The Time Traveler's Wife (2009) (completed) .... Clare Abshire
  
• The Lucky Ones (2008) .... Colee Dunn
• Married Life (2007) .... Kay Nesbitt
• The Family Stone (2005) .... Amy Stone
• Red Eye (2005) .... Lisa Reisert
• Wedding Crashers (2005) .... Claire Cleary
• "Slings and Arrows" .... Kate McNab (7 episodes, 2003-2005)
       - Season's End (2005) TV episode .... Kate McNab
       - Playing the Swan (2003) TV episode .... Kate McNab
       - Mirror up to Nature (2003) TV episode .... Kate McNab
       - Outrageous Fortune (2003) TV episode .... Kate McNab
       - Madness in Great Ones (2003) TV episode .... Kate McNab
        (2 more)
• The Notebook (2004) .... Allie Hamilton
• Mean Girls (2004) .... Regina George
  ... aka Méchantes ados (Canada: French title)
• The Hot Chick (2002) .... Jessica
• Perfect Pie (2002) .... Patsy (age 15)
  ... aka Voie du destin, La (Canada: French title)
• My Name Is Tanino (2002) .... Sally Garfield
• Guilt by Association (2002) (TV) .... Danielle
  ... aka Coupable par amour (Canada: French title)
• "Earth: Final Conflict" .... Christine Bickwell (1 episode, 2002)
  ... aka EFC (USA: promotional abbreviation)
  ... aka Gene Roddenberry's Earth: Final Conflict (USA: complete title)
  ... aka Invasion planète Terre (Canada: French title)
  ... aka Mission Erde: Sie sind unter uns (Germany)
       - Atavus High (2002) TV episode (as Rachel MacAdams) .... Christine Bickwell
• "The Famous Jett Jackson" .... Hannah Grant (1 episode, 2001)
       - Food for Thought (2001) TV episode .... Hannah Grant
• Shotgun Love Dolls (2001) (TV) .... Beth