Nonsteroidal anti-inflammatory drugs (NSAIDs) have unacceptable morbidity and mortality due to their gastrointestinal toxicity. Attempts so far to improve the safety profile of NSAIDs have met with limited clinical acceptance. Nitric oxide (NO) functions as an endogenous mediator of gastric mucosal health and defense. Recent medicinal chemistry approaches attempt to exploit the tissue-protective function of NO against NSAID-induced gastric injury. Both nitroxybutyl-ester and nitrosothiol NSAID derivatives have been synthesized. Profiling of these NO-donating NSAIDs in both the laboratory and the clinic suggests that they might offer a unique solution to the problem of NSAID-induced gastropathy without sacrificing the well-accepted pharmacological activity of these agents in the management of pain and inflammation.