Diarrhea is common among hospitalized patients but the causes are distinct from those of diarrhea in the community. We review existing data about the epidemiology of nosocomial diarrhea and summarize recent progress in understanding the mechanisms of diarrhea. Clinicians should recognize that most cases of nosocomial diarrhea have a noninfectious etiology, including medications, underlying illness, and enteral feeding. Apart from Clostridium difficile, the frequency of infectious causes such as norovirus and toxigenic strains of Clostridium perfringens, Klebsiella oxytoca, Staphylococcus aureus, and Bacteroides fragilis remains largely undefined and test availability is limited. Here we provide a practical approach to the evaluation and management of nosocomial diarrhea when tests for C. difficile are negative.