Clostridium perfringens alpha-toxin is thought to be an important agent in gas gangrene, which is a lifethreatening infection with fever, pain, edema, myonecrosis, and gas production. The toxin (370 residues) is composed of an N-terminal domain (1-250 residues, N-domain) in which the catalytic site is found and a C-terminal domain (251-370 residues, C-domain) responsible for binding to membranes. During the past decade, recombinant DNA technology has been employed to develop second-generation vaccines, including site-directed mutants and the C-domain of the toxin, to prevent gas gangrene. These immunities have led to protection against the lethal effects of wild-type C. perfringens in mice. C-domain vaccines are capable of protecting against heterologous clostridia causing clostridial myonecrosis. This article summarizes the current knowledge on vaccines against alpha-toxin.