Gastrointestinal disease is a significant cause of morbidity and mortality in the immunocompromised patient. This article focuses on the infectious gastrointestinal complications associated with the treatment of malignant disease and with solid organ transplantation but not HIV. Gastrointestinal defenses and the various mechanisms by which they are impaired are reviewed. The major pathogens and malignancies of this patient population and an approach to their diagnosis, treatment, and prevention are discussed.