Sulfide is a molecule with toxicity comparable to that of cyanide. It inhibits mitochondrial cytochrome oxidase at submicromolar concentrations. However, at even lower concentrations, sulfide is a substrate for the mitochondrial electron transport chain in mammals, and is comparable to succinate. This oxidation involves a sulfide quinone reductase. Sulfide is thus oxidized before reaching a toxic concentration, which explains why free sulfide concentrations are very low in mammals, even though sulfide is constantly released as a result of cellular metabolism. It has been suggested that sulfide has signaling properties in mammals like two other gases, NO and CO, which are also cytochrome oxidase inhibitors. The oxidation of sulfide by mitochondria creates further complexity in the description/use of sulfide signaling in mammals. In fact, in the many studies reported in the literature, the sulfide concentrations that have been used were well within the range that affects mitochondrial activity. This review focuses on the relevance of sulfide bioenergetics to sulfide biology and discusses the case of colonocytes, which are routinely exposed to higher sulfide concentrations. Finally, we offer perspectives for future studies on the relationship between the two opposing aspects of this Janus-type molecule, sulfide.