As we approach the 100th year since the introduction of aspirin to the marketplace, the association of gastrointestinal damage with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) remains the major limitation to their use. Although various approaches have been taken to producing NSAIDs with reduced gastrointestinal toxicity, few have significantly reduced the incidence of clinically significant adverse reactions (perforation or hemorrhage). In this review, the mechanisms contributing to the mucosal injury caused by NSAIDs in the stomach, small intestine, and colon are reviewed. In addition, several recent strategies for developing NSAIDs that spare the gastrointestinal tract of injury are discussed. These include selective inhibitors of cyclooxygenase 2, nitric oxide-releasing NSAIDs, and NSAIDs preassociated with zwitterionic phospholipids.