Nel 2001 recita ne La rivincita delle bionde con Reese Witherspoon e di seguito La cosa più dolce... Nel 2004 interpreta Elizabeth Sherman in Hellboy di Guillermo del Toro, e prende parte anche a film come In Good Company e A Dirty Shame di John Waters, in seguito ha recitato in film come The Fog - Nebbia assassina, Purple Violets e Hellboy: The Golden Army.
Alec Baldwin gave her a favorable review – he called her "a cross between Debra Winger and Marlene Dietrich".Later, she was selected to take the lead in the fantasy film Amazon High alongside Karl Urban.Later, Blair starred in other notable films including Down to You (2000), Legally Blonde (2001) and The Sweetest Thing (2002).She achieved international fame as a result of her portrayal of the heroine Liz Sherman in the fantasy films Hellboy (2004) and Hellboy II: The Golden Army (2008).The film had a limited release in September 2001 in New York and Los Angeles.
In the second half of 2001, Blair co-starred in the comedy Legally Blonde opposite Reese Witherspoon.
The second season was just renamed Zoe..., which follows the title character a few years later as a psychology student; the show was not renewed for a third season.
She was nominated for the Teen Choice Awards for "TV – Breakout Performance" category for her role in Zoe, Duncan, Jack & Jane.
È stata sposata, dal 2004 al 2006, con il musicista e produttore discografico Ahmet Zappa, figlio del celebre Frank Zappa.
Dal 2010 al settembre del 2012 è stata legata allo stilista Jason Bleick, da cui ha avuto un figlio, Arthur Saint, nato il 25 luglio del 2011.
Blair starred as a present-day orphaned high school student who accidentally travels back in time to the mythical days of the Amazons.