The nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs in the world. Their use as anti-inflammatory, antipyretic, antithrombotic, and analgesic agents is, however, restricted by their adverse effects on gastrointestinal (GI) tract. To overcome this problem with NSAIDs, two new strategies in the development of these drugs are explained. The first approach is the development of selective inhibitors of the enzyme cyclooxygenase (COX)-2, the inducible isoform of the prostaglandin G/H synthetase enzyme. COX exists in two isoforms, viz., COX-1 and COX-2. Selective inhibitors of COX-2 will suppress prostaglandin synthesis at the sites of inflammation, but they will not interfere with the activity of COX-1, in tissues like the GI tract. The use of selective COX-2 inhibitors, however, lacks the cardioprotective effects mediated by COX-1. An alternate approach to reduce the GI toxicity of NSAIDs is the development of nitric oxide (NO)-releasing NSAIDs. It has been reported that NO does not affect the gastroduodenal mucosa and produces the same effects as endogenous prostaglandins. The present article focuses on the NO-releasing NSAIDs, which are from the conventional class of COX-2 inhibitors that have potential clinical applications, as well as some drug candidates still under development.