Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most commonly used drugs in the Western world. Patients undergoing NSAID therapy often experience abdominal discomfort, and some of them develop serious complications, such as ulceration, perforation, or bleeding. Since serious complications of NSAID therapy can occur in relatively asymptomatic patients and abdominal symptoms do not serve as a signal of impending difficulties, there is a need for methods to identify those patients who may benefit from prophylactic therapy to prevent NSAID-induced injury. Therapy to prevent NSAID-associated gastrointestinal ulcerations is most effective when prostaglandins are used. H2-receptor antagonists prevent duodenal ulcerations but not gastric ulcerations. The role of omeprazole (hydrogen-potassium pump inhibitor) and sucralfate in the prevention of gastroduodenal ulcerations has not been firmly established. Healing of existing ulcerations in the face of continuing therapy with NSAIDs is marginally accelerated by H2-receptor antagonists, but the rate of healing in the presence of continued NSAID therapy is much slower than when NSAIDs are discontinued. Omeprazole may prove to accelerate the healing of NSAID-associated ulcerations even when NSAID therapy is continued, but more information is needed to substantiate this possibility. New methods are needed for early noninvasive detection of mucosal damage by NSAIDs and for the identification of individuals who should receive prophylactic therapy. New agents are also needed to provide cost-effective prophylaxis against the development of ulcerations and serious complications from NSAIDs.