Clostridium difficile infections (CDIs) are increasingly a cause of morbidity and mortality. Although the pathogenicity of C difficile is based on toxin A and B expression, new hypervirulent strains express novel virulence factors. The etiology of recent increases in prevalence and severity of disease is not clearly explained by known mechanisms. New at-risk groups include children (without prior antibiotic exposure) and patients with inflammatory bowel disease. Vancomycin has an important role in the treatment of CDIs, but does not prevent recurrence. Other therapies for recurrent disease include antibiotics, probiotics, and immunotherapy. Novel therapies are under investigation for recurrent and resistant CDI. Copyright © 2009 by Lippincott Williams & Wilkins.