Like nitric oxide and carbon monoxide, hydrogen sulfide has historically been recognized as an industrial pollutant, but in recent years, it has been shown to be an important mediator of many physiological processes. Hydrogen sulfide contributes to the maintenance of gastrointestinal mucosal defense and repair. It also exerts many antiinflammatory effects, including inhibition of leukocyte adherence to the vascular endothelium and leukocyte migration to sites of inflammation. Conversely, inhibition of endogenous hydrogen sulfide synthesis leads to a loss of mucosal integrity and to an increase in mucosal inflammation. Hydrogen sulfide therefore appears to have overlapping actions with nitric oxide and prostaglandins in terms of modulating mucosal defense and resolution of inflammation. Recent evidence suggests that these properties of hydrogen sulfide can be exploited in the design of novel therapies for ulcerative and inflammatory diseases of the gastrointestinal tract.