After working on the television series As the World Turns, Tomei came to prominence as a cast member on The Cosby Show spin-off A Different World in 1987. After having minor roles in a few films, she came to international attention in 1992 with the comedy My Cousin Vinny, for which she received the Academy Award for Best Supporting Actress. She received two additional Academy Award nominations for In the Bedroom (2001) and The Wrestler (2008).
Tomei has appeared in a number of successful movies, including What Women Want (2000), Anger Management (2003), Wild Hogs (2007), The Ides of March (2011), and Parental Guidance (2012). Other films include Untamed Heart (1993), Only You (1994), The Paper (1994), Unhook the Stars (1996), Slums of Beverly Hills (1998), Before the Devil Knows You’re Dead (2007), Cyrus (2010), Lincoln Lawyer (2011), Love Is Strange (2014), The Big Short (2015), The First Purge (2018) and The King of Staten Island (2020). She also portrays May Parker in the Marvel Cinematic Universe, having appeared in Captain America: Civil War (2016), Spider-Man: Homecoming (2017), Avengers: Endgame (2019), and Spider-Man: Far From Home (2019), she will return as the character in Spider-Man: No Way Home (2021).
Tomei has also worked in theater. She was formerly involved with the Naked Angels Theater Company and appeared in plays, such as Daughters (1986), Wait Until Dark (1998), Top Girls (2008), for which she received a nomination for the Drama Desk Award for Outstanding Featured Actress in a Play, and The Realistic Joneses (2014), for which she received a special award at the Drama Desk Awards.