Hydrogen sulfide (H2S) is produced in the gut from cysteine by epithelial cells and by the intestinal microbiota. Initially considered as a toxic gas, the pleiotropic effects of H2S are now recognized, especially in the colonic mucosa. The aim of this review is to present new experimental data indicating that cysteine-derived H2S is emerging as a key regulator of gut health. Cysteine degradation by the microbiota emerged as a dominant pathway for H2S production. Among bacteria producing H2S from cysteine, Fusobacterium appears as a pivotal genus associated with digestive diseases. H2S promotes or alleviates mucosal inflammation, mostly according to its high (high micromolar to millimolar) or low (nanomolar to low micromolar) concentration, respectively. H2S maintains the integrity of the mucus layer when derived from endogenous metabolism but is detrimental for this parameter when produced in excess by gut microbes. In inflammatory bowel diseases, an upregulation of H2S production from cysteine by the gut microbiota is observed concomitantly with a downregulation of enzymes implicated in its mucosal detoxification. In colorectal cancer patients, an upregulation of both endogenous and microbial H2S production from cysteine are observed at tumor site that might contribute to disease progression. H2S is a double-edge sword for the intestinal epithelium. This is related to the bell-shaped effects of H2S, with protective effect at low concentration but deleterious effects at higher concentrations. As the gut microbiota produces much more H2S from cysteine than endogenous metabolism, we consider that the bacterial or epithelial source of H2S is a major determinant of its effects for intestinal health.