Hydrogen sulfide (H 2 S) is a familiar toxic gas that smells of rotten eggs. After the identification of endogenous H 2 S in the mammalian brain two decades ago, studies of this molecule uncovered physiological roles in processes such as neuromodulation, vascular tone regulation, cytoprotection against oxidative stress, angiogenesis, anti-inflammation, and oxygen sensing. Enzymes that produce H 2 S, such as cystathionine O-synthase, cystathionine .-lyase, and 3-mercaptopyruvate sulfurtransferase have been studied intensively and well characterized. Polysulfides, which have a higher number of inner sulfur atoms than that in H 2 S, were recently identified as potential signaling molecules that can activate ion channels, transcription factors, and tumor suppressors with greater potency than that of H 2 S. This article focuses on our contribution to the discovery of these molecules and their metabolic pathways and mechanisms of action.