Nonsteroidal anti-inflammatory (NSAID) drugs have been used to treat osteoarthritis ever since 1899, when the effects of aspirin were first recognized. Widespread use of these compounds continues despite their recognized potential toxicity, mostly because they are generally effective for palliation of the pain associated with osteoarthritis. The discovery of cyclooxygenase (COX)-1 and COX-2 has sparked interest in development of NSAID that specifically target COX-2, with the hope that such compounds would be associated with a lower incidence of adverse gastrointestinal effects. Other potential methods of avoiding adverse gastrointestinal effects associated with NSAID use include concurrent administration of prostaglandins and use of pure analgesics, such as acetaminophen. The role of nitric oxide in inflammation is an exciting area of research, and addition of nitric oxide-producing moieties to NSAID may prove to be another mechanism of avoiding gastrointestinal toxicity. There is likely to be considerable reward for the development of an NSAID that relieves pain associated with a wide variety of conditions, does not cause gastrointestinal toxicoses, and spares normal cartilage. Whether such a drug exists remains speculative.