C. difficile is a frequent cause of nosocomial diarrhea and is associated with substantial morbidity. C. difficile carriage may arise either from overgrowth of endogenous organisms or from exogenous acquisition. Within hospitals, asymptomatically colonized patients typically outnumber symptomatic patients by a ratio of approximately 3:1. Patient-to-patient transmission of C. difficile has been well documented in studies of nosocomial outbreaks, utilizing typing methods to supplement epidemiologic investigations. The mechanisms and frequency of transmission probably vary between institutions, but contamination of environmental surfaces and personnel hand carriage both appear to be important. Nosocomial C. difficile infection can be remarkably difficult to control, particularly after it becomes endemic in an institution. Policies targeting both environmental contamination and personnel hand-washing/glove use practices may be most successful. Prophylaxis of C. difficile diarrhea in high-risk patients on antibiotics may also have merit if an effective and safe biologic agent can be identified. Asymptomatically colonized patients should not be treated because they are at low risk for the development of diarrhea and because further antibiotic treatment may prolong the carrier state.