Nonsteroidal anti-inflammatory drugs are widely used for the treatment of osteoarthritis and rheumatoid arthritis, but their ability to cause gastrointestinal bleeding is a significant limitation to this use. A better understanding of the pathogenesis of gastric and intestinal injury induced by these agents will permit the rational design of anti-inflammatory drugs that spare the gastrointestinal tract. In this review, the mechanisms through which nonsteroidal anti-inflammatory drugs are believed to cause gastrointestinal ulceration are reviewed. Several strategies that are being employed to develop gastrointestinal-sparing drugs are outlined.