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Callies was born in La Grange, Illinois and moved to Honolulu, Hawaii with her family when she was one year old. Her parents are professors at the University of Hawaii, Manoa, but Callies did not follow in their footsteps. Instead, she chose to pursue a career in acting.
Throughout her youth, she expressed an interest in acting through participating in various school plays at the independent Punahou School. After graduating from high school, she entered Dartmouth College in Hanover, New Hampshire. In conjunction with her studies, she continued her involvement in theatre. She continued her education at Denver's National Theater Conservatory, where she obtained her Master of Fine Arts degree in 2002.
Callies' first role on television was as Kate O'Malley, a recurring role on the short-lived CBS show Queens Supreme. Her first starring role was as Detective Jane Porter on The WB's Tarzan. After making various guest appearances on Law & Order: Special Victims Unit, Dragnet (2003) and NUMB3RS, Callies gained a starring role on Fox's Prison Break as Sara Tancredi. Her role lasted from 2005 through 2009.
Callies has also starred in two feature films - Universal Pictures' Whisper and an independent film, The Celestine Prophecy. In April 2010, she appeared on the Fox Television drama House M.D. as a patient of the week whose open marriage fascinates House and the team.
She portrayed Lori Grimes in the AMC horror/drama series The Walking Dead, based on the comic book series of the same name up until her character's death. Callies played one of the female lead roles in the Canadian thriller Faces in the Crowd. In August 2010 Callies' first screenplay, an adaptation of Campbell Geeslin's children's book "Elena's Serenade", was optioned by producer Cameron Lamb and Canadian production company The Film Farm. Callies also starred in the movie Black Gold.
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