Enterotoxemia is a common, frequently fatal disease of small ruminants caused by enteric superinfection with Clostridium perfringens. C. perfringens type C causes hemorrhagic enteritis of lambs. Type D causes colitis in goats and rapidly progressive, multi-organ failure in sheep, characterized by recumbency, convulsions, and opisthotonus. Prevention of enterotoxemia requires careful attention to feeding practices such that sudden ingestion of large quantities of concentrates or protein does not occur. Diligent vaccination is the cornerstone to enterotoxemia prevention; however, sheep and goats differ in their immune responses to conventional vaccines, and different vaccination regimens are necessary for these two species.