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In January 2005, she began starring in her first television series, NBC's Medium.

Her role as ( a fictionalized version of ) psychic medium Allison DuBois won her an Emmy Award for Outstanding Lead Actress in 2005, as well as nominations for a Golden Globe in 2005, 2006 and 2007, a SAG Award in 2006 and 2010, and an Emmy Award in 2007.

In 2009 NBC cancelled Medium, then CBS picked the show up and it lasted another two seasons.

By 2011 she was earning $ 225, 000 per episode for the series.

Arquette played the role of Allison DuBois until 2011 when CBS cancelled the series.

The final episode of Medium aired on January 21, 2011.