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Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications-both prescription and over the counter-in the United States. Gastrointestinal side effects from NSAIDs are responsible for significant patient morbidity and mortality as well as healthcare cost. With the development of cyclooxygenase-2 (COX-2) specific inhibitors, these serious adverse reactions have been significantly reduced without affecting therapeutic benefit; however, the need for careful monitoring of patients on therapy with traditional NSAIDs and COX-2 inhibitors continues. In this article, recent developments regarding COX-2 inhibitors and potential future uses of this class of drugs are also discussed.