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In her native United States, Dudek has since guest starred on other TV shows, including Desperate Housewives (as Karl Mayer's girlfriend in Season 1), How I Met Your Mother (as Ted's Krav Maga-trained ex-girlfriend), Friends (as 'Precious', Mike Hannigan's girlfriend), ER (as a mother who accidentally shot her son), Charmed, Bones (as Seeley Booth's lawyer girlfriend), Numb3rs, and Six Feet Under.
She also played Lucinda Barry in the pilot episode of Psych, and a teacher who has a sexual relationship with one of her students (based on the case of Debra Lafave) on Law & Order: Criminal Intent.
In 2012, she played an ISS astronaut in one episode of the TV show Touch.
She also founded a production company Calamity Jane.She made her second appearance in Law & Order in 2000, and then guest-starred on Strangers with Candy, Strong Medicine and Friends.In 2002, Pompeo was selected by director Brad Silberling for a lead role in his film Moonlight Mile, playing Jake Gyllenhaal's character's sympathetic love interest.Although her scenes were cut from that film, she felt grateful that director Michel Gondry selected her for his film.Pompeo landed her first major role in 2005 on the ABC medical drama series Grey's Anatomy, created by Shonda Rhimes.