Nonsteroidal anti-inflammatory drugs are widely used for the treatment of chronic arthropathies, but their gastrointestinal damage remains a significant limitation to their use. In this review, the pathogenic mechanisms through which these drugs are believed to cause gastrointestinal damage are outlined. A better understanding of the pathogenesis of gastric and intestinal injury has resulted in novel strategies that are being employed to develop nonsteroidal anti-inflammatory drugs that do not have significant adverse effects on the gastrointestinal tract.