Clostridium difficile, the bacterium responsible for antibiotic-associated diarrhea and colitis, has become a significant cause of morbidity and prolonged hospital stays, largely because of the increasing use of broad-spectrum antibiotics. This gram-positive organism, which can lay dormant in its spore form in the environment for extended periods of time, proliferates in the colon when the normal colonic flora is compromised by antibiotic use. C. difficile produces intestinal inflammation and diarrhea through the elaboration of two protein exotoxins, toxin A and toxin B. The spectrum of clinical manifestations ranges from mild diarrhea that resolves with the cessation of the offending antibiotic, to fulminant pseudomembranous colitis complicated by megacolon and perforation. Our ability to meet the challenge offered by this organism has been enhanced by the development of new diagnostic modalities as well as the development of new therapeutic regimens. Through further investigation of the structure and function of toxins A and B and further study of the interaction of C. difficile with the normal colonic flora, advances will continue to be made in the prevention and treatment of antibiotic-associated colitis.