Her subsequent film roles include He Got Game (1998), Josie and the Pussycats (2001), Men in Black II (2002), The Rundown (2003), Rent (2005), Sin City (2005), Clerks II (2006), Death Proof (2007), Seven Pounds (2008), Percy Jackson & the Olympians: The Lightning Thief (2010), Unstoppable (2010), Zookeeper (2011), Trance (2013), Top Five (2014), Zombieland: Double Tap (2019), and Clerks 3 (2022).

These include Gail in Sin City (2005) and Sin City: A Dame to Kill For (2014), Claire Temple in five of the Marvel Netflix series (2015–2018), and providing the voices of Diana Prince / Wonder Woman in the DC Animated Movie Universe and Space Jam: A New Legacy and Barbara Gordon / Batgirl in The Lego Batman Movie.

[4] Isabel and Greg moved into a reclaimed building on East 13th Street after being approved as members of an affordable housing plan.

[14] She is also featured on the track "She Lives In My Lap" from the second disc of the OutKast album Speakerboxxx/The Love Below,[15] in which she speaks the introduction and a brief interlude towards the end.

In 2001, she appeared in the film Josie and the Pussycats as band member Valerie Brown and had a role in Chelsea Walls, the directorial debut of Ethan Hawke.

In 2005, Dawson made her stage debut[16] as Julia in the Public Theater's "Shakespeare in the Park" revival of Two Gentlemen of Verona.

She also appeared in the adaptation of the graphic novel Sin City, co-directed by Robert Rodriguez and Frank Miller, portraying Gail, a prostitute-dominatrix.

She co-starred with former Rent alumna Tracie Thoms in the Quentin Tarantino throwback film Death Proof in 2007, part of the Tarantino/Robert Rodriguez double feature Grindhouse.

[22] In 2009, Dawson also voiced the character of Velvet Von Black in Rob Zombie's animated feature, The Haunted World of El Superbeasto.

In 2010, she starred in the films Percy Jackson & the Olympians: The Lightning Thief as Persephone, and Unstoppable as railway yardmaster Connie Hooper.

In 2015, she played Claire Temple in the Netflix web television series Daredevil, a role which she reprised in Jessica Jones and Luke Cage.

[23] She appeared in Top Five in 2014, for which she was nominated for the Critics' Choice Movie Award for Best Actress in a Comedy, and in 2018, she played the female lead role in the film Krystal.

[32] Dawson is involved with the Lower East Side Girls Club[33] and supports other charities such as environmental group Global Cool, One Campaign, Oxfam, Operation USA, Amnesty International, Parents, Families and Friends of Lesbians and Gays (PFLAG), the International Rescue Committee, Voto Latino,[34] and Stay Close.org, a poster and public service advertising campaign for PFLAG, where she is featured with her uncle[35] Frank Jump.

[36] She has participated in the Vagina Monologues[37] and serves on the board for V-Day, a global non-profit movement that raises funds for women's anti-violence groups through benefits of this play.

In 2012, Dawson partnered with SodaStream International in launching the first annual Unbottle the World Day, a campaign conceived in an effort to raise awareness to the impact of cans and plastic bottles on the environment.

[44][45][46] In 2018, Dawson made a post to Instagram that was widely perceived as her coming out as queer; when asked about this in a 2020 interview, she stated that this had not been her intention, and further specified that although "People kept saying that I [came out]...