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Nitric oxide (NO) is now recognized as an important modulator of an enormous number of physiological processes, ranging from blood pressure regulation to neuronal transmission to penile erectile function. In the gastrointestinal tract, NO also participates in many physiological and pathophysiological processes. In this review, we summarize the contribution made by NO to the ability of the gastrointestinal mucosa to resist injury induced by luminal toxins and to defend against microbial invasion. We also review some of the main features of NO chemistry and the potential of NO as a target for new drugs to treat gastrointestinal disorders.