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Kanakaredes' first major role was on the daytime drama Guiding Light, originating the role of Eleni Andros Spaulding Cooper from 1991 to 1995. She was nominated twice for Daytime Emmy Awards for her portrayal of Eleni. Her most high-profile roles on television were as series protagonist Dr. Sydney Hansen on Providence, which ran for five seasons (from 1999–2002), and since 2004 in a leading role on the CBS show CSI: NY, as detective Stella Bonasera.

Her other television credits include NYPD Blue, Northern Exposure, Due South, Oz, The Practice, and the Hallmark Hall of Fame presentation of Saint Maybe. Her appearances in film include The Long Kiss Goodnight as Trin and 15 Minutes as Nicolette Karas, the girlfriend of Robert DeNiro's character. She was considered for the lead role in My Big Fat Greek Wedding but had to turn it down due to pregnancy.