Clostridial myonecrosis remains an important cause of human morbidity and mortality worldwide. Although traumatic gas gangrene can be readily diagnosed from clinical findings and widely available technologies, spontaneous gas gangrene is more insidious, and gynecologic infections due to Clostridium sordellii progress so rapidly that death often precedes diagnosis. In each case, extensive tissue destruction and the subsequent systemic manifestations are mediated directly and indirectly by potent bacterial exotoxins. The management triumvirate of timely diagnosis, thorough surgical removal of necrotic tissue, and treatment with antibiotics that inhibit toxin synthesis remains the gold standard of care. Yet, despite these measures, mortality remains 30% to 100% and survivors often must cope with life-altering amputations. Recent insights regarding the genetic regulation of toxin production, the molecular mechanisms of toxin-induced host cell dysfunction, and the roles of newly described toxins in pathogenesis suggest that novel prevention, diagnostic, and treatment modalities may be on the horizon for these devastating infections.