Clostridium difficile causes pseudomembranous colitis in humans, usually after disruption of the bowel flora by antibiotic therapy. Factors mediating the frank disease include the dose and toxigenicity of the colonizing strain, its ability to adhere to colonic epithelium, the concurrent presence of organisms that affect multiplication and toxin production or activity, and the susceptibility of the host. Toxins A (an enterotoxin) and B (a cytotoxin) play the major role in pathogenesis and the detection of toxins in gut contents is the gold standard for diagnosis. Disease in horses takes the form of often-fatal foal hemorrhagic enteritis. Nosocomial, antibiotic-associated, disease is increasingly common in adult horses. Enteric clinical signs are reported in ostriches, companion animals and recently calves. Clostridium difficile colitis is now a common diagnosis in neonatal pigs in the USA and elsewhere. Clinical features include onset at 1–5 days of age, sometimes with dyspnea, mild abdominal distension and scrotal edema, and commonly with yellow, pasty diarrhea. There is mesocolonic edema grossly, with microscopic diffuse colitis, mucosal edema, crypt distension, epithelial necrosis and superficial mucosal erosion. Neutrophil infiltration of the lamina propria is common, and fibrin and numerous rod-shaped bacteria are observed on the surface. About two-thirds of litters and one-third of piglets will be affected (based upon positive toxin tests), although this appears to vary with the season. The case fatality rate is probably low if considering only direct effects of C. difficile infection. The significance of toxin-positive non-diarrheic pigs and the nature of the interaction of toxins A and B with enterocytes are unknown. Given the widespread occurrence of the disease, there is substantial effort to develop immunoprophylactic products.