In humans and livestock, Clostridium perfringens is an important cause of intestinal infections that manifest as enteritis, enterocolitis, or enterotoxemia. This virulence is largely related to the toxin-producing ability of C. perfringens. This article primarily focuses on the C. perfringens type F strains that cause a very common type of human food poisoning and many cases of nonfoodborne human gastrointestinal diseases. The enteric virulence of type F strains is dependent on their ability to produce C. perfringens enterotoxin (CPE). CPE has a unique amino acid sequence but belongs structurally to the aerolysin pore-forming toxin family. The action of CPE begins with binding of the toxin to claudin receptors, followed by oligomerization of the bound toxin into a prepore on the host membrane surface. Each CPE molecule in the prepore then extends a beta-hairpin to form, collectively, a beta-barrel membrane pore that kills cells by increasing calcium influx. The cpe gene is typically encoded on the chromosome of type F food poisoning strains but is encoded by conjugative plasmids in nonfoodborne human gastrointestinal disease type F strains. During disease, CPE is produced when C. perfringens sporulates in the intestines. Beyond type F strains, C. perfringens type C strains producing beta-toxin and type A strains producing a toxin named CPILE or BEC have been associated with human intestinal infections. C. perfringens is also an important cause of enteritis, enterocolitis, and enterotoxemia in livestock and poultry due to intestinal growth and toxin production.