The pathogenesis of clostridial myonecrosis or gas gangrene involves an interruption to the blood supply to the infected tissues, often via a traumatic wound, anaerobic growth of the infecting clostridial cells, the production of extracellular toxins, and toxin-mediated cell and tissue damage. This review focuses on host-pathogen interactions in Clostridium perfringens-mediated and Clostridium septicum-mediated myonecrosis. The major toxins involved are C. perfringens α-toxin, which has phospholipase C and sphingomyelinase activity, and C. septicum α-toxin, a β-pore-forming toxin that belongs to the aerolysin family. Although these toxins are cytotoxic, their effects on host cells are quite complex, with a range of intracellular cell signaling pathways induced by their action on host cell membranes.