Hydrogen sulfide, like nitric oxide, was best known as a toxic pollutant before becoming recognized as a key regulator of several physiologic processes. In recent years, evidence has accumulated to suggest important roles for hydrogen sulfide as a mediator of several aspects of gastrointestinal and liver function. Moreover, alterations in hydrogen sulfide production could contribute to disorders of the gastrointestinal tract and liver. For example, nonsteroidal anti-inflammatory drugs can reduce production of hydrogen sulfide in the stomach, and this has been shown to contribute to the generation of mucosal injury. Hydrogen sulfide has also been shown to play a key role in modulation of visceral hyperalgesia. Inhibitors of hydrogen sulfide synthesis and drugs that can generate safe levels of hydrogen sulfide in vivo have been developed and are permitting interventional studies in experimental models and, in the near future, humans.