BACKGROUND: The term stress-related mucosal disease (SRMD) represents a continuum of conditions ranging from stress-related injury (superficial mucosal damage) to stress ulcers (focal deep mucosal damage). Caused by mucosal ischemia, SRMD is most commonly seen in critically ill patients in the intensive care unit (ICU). Prophylaxis of stress ulcers may reduce major bleeding but has not yet been shown to improve survival. OBJECTIVES: This article reviews currently available agents for the prophylaxis of SRMD and discusses their uses and potential adverse effects. METHODS: Relevant articles in the English-language literature were identified through a MEDLINE search (1968-2003) using the key words stress-related mucosal disease, stress-related injury, ulcer, prophylaxis, intensive care unit, and upper gastrointestinal bleeding. RESULTS: The most widely used drugs for stress-related injury are the intravenous histamine(2)-receptor antagonists. These drugs raise gastric pH but are associated with the development of tolerance and possible drug interactions and neurologic manifestations. Sucralfate, which can be administered by the nasogastric route, can protect the gastric mucosa without raising pH, but may decrease the absorption of concomitantly administered oral medications. The prostaglandin misoprostol has not been shown to be of benefit in the prophylaxis of SRMD. Antacids lower the risk of gastrointestinal bleeding, but large volumes of antacids are required and treatment is labor intensive. Proton pump inhibitors (PPIs) are the most potent acid-suppressive pharmacologic agents available. Esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole substantially raise gastric pH for up to 24 hours after a single dose. The availability of an intravenous formulation of pantoprazole may help improve the treatment of SRMD in ICU patients, particularly those receiving mechanical ventilation. Tolerance does not develop, and few adverse effects have been reported. CONCLUSIONS: Recent studies of PPIs have shown promising results in high-risk patients, making this class of drugs an option for the prophylaxis of SRMD.