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The series follows Sara Pezzini, a tough-as-nails NYPD homicide  detective  who comes into possession of the Witchblade, a supernatural, sentient  artifact with immense destructive and protective powers. The weapon has bonded with various other women throughout history, the most recent being the series" former co-lead, Danielle Baptiste. Others who have come into contact with the Witchblade include Cleopatra and Joan of Arc. Sara struggles to hone the awesome powers of the Witchblade and fend off those with a nefarious interest in it, especially entrepreneur Kenneth Irons. She also struggles to maintain a personal life.

There have been many spin-off titles which place the Witchblade in other times and settings. The character of Sara Pezzini was also featured in crossovers with characters from other franchises, including Lara Croft, the Justice League, and the cast of Battle of the Planets.