Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed medications, but their use continues to be limited by significant toxicity, particularly in the gastrointestinal tract and kidney. Better understanding of the pathogenesis of these adverse effects has led to the development of a series of derivatives of standard NSAIDs that are not only less toxic but more efficacious. The coupling of a nitric oxide-releasing moiety to a range of NSAIDs greatly reduces their ability to induce gastrointestinal damage, and greatly increases their tolerability in situations in which there is preexisting gastrointestinal inflammation. There is also evidence that these compounds are much better tolerated by the kidney. On the other hand, the analgesic and anti-thrombotic properties of NO-releasing NSAIDs significantly exceed those of the parent drugs. These compounds appear to represent a significant advance in the treatment of inflammation and pain and for prophylaxis of thrombotic conditions. Drug Dev. Res. 42:144-149, 1997.