Significance: Hydrogen sulfide is emerging as an important mediator of many aspects of inflammation, and perhaps most importantly as a factor promoting the resolution of inflammation and repair of injury. Recent Advances: In the gastrointestinal tract, H2S has been shown to promote healing of ulcers and the resolution of mucosal inflammation. On the other hand, suppression of endogenous H2S synthesis impairs mucosal defense and leads to increased granulocyte infiltration. H2S has been exploited in the design of more effective and safe anti-inflammatory drugs. Critical Issues: Enteric bacteria can be a significant source of H2S, which could affect mucosal integrity; indeed, luminal H2S can serve as an alternative to oxygen as a metabolic substrate for mitochondrial respiration in epithelial cells. Enterocytes and colonocytes thereby represent a “metabolic barrier” to the diffusion of bacteria-derived H2S into the subepithelial space. A compromise of this barrier could result in modulation of mucosal function and integrity by bacterial H2S. Future Directions: Improvements in methods for measurement of H2S and development of more selective inhibitors are crucial for gaining a better understanding of the pathophysiological importance of this mediator. Results from animal studies suggest that H2S-releasing agents are promising therapeutic agents for many indications, but these compounds need to be assessed in a clinical setting. Antioxid. Redox Signal. 17, 58–67.