Clostridium perfringens gas gangrene is, without a doubt, the most fulminant necrotizing infection that affects humans. In victims of traumatic injury, the infection can become well established in as little as 6-8 h, and the destruction of adjacent healthy muscle can progress several inches per hour despite appropriate antibiotic coverage. Shock and organ failure are present in 50% of patients and, among these, 40% die. Despite modern medical advances and intensive-care regimens, radical amputation remains the single best life-saving treatment. Over the past century, much has been learned about the pathogenesis of this disease, and novel therapies are on the horizon for patients with this devastating infection.