Clostridium difficile infection (CDI) is the most important cause of nosocomial diarrhea. The emergence of a hypervirulent strain and other factors including antibiotic overuse contribute to the increasing incidence and severity of this potentially lethal infection. CDI has been reported in persons previously considered as low risk, such as young healthy persons without exposure to health care settings or antibiotics, peripartum women, and children. In patients with inflammatory bowel disease, the risk of C. difficile infection is even greater, with higher rates of hospitalization, bowel surgery, and mortality. With increasing incidence and severity of disease, the need for improved diagnostic, treatment, and infection control strategies cannot be overstated.