The first endothelium-derived relaxing factor (EDRF) ever identified is a gasotransmitter, nitric oxide (NO). Recent studies have provided several lines of evidence to support the premise that hydrogen sulfide (H2S), another gasotransmitter, is a new EDRF. H2S production is catalyzed in mammalian cells by cystathionine β-synthase (CBS) and/or cystathionine γ-lyase (CSE). The expression of CSE proteins and the activity of CBS have been observed in vascular endothelial cells. A measurable amount of H2S is produced from endothelium upon muscarinic cholinergic stimulation. The endothelium-dependent vasorelaxation induced by H2S shares many common mechanistic traits with those of endothelium-derived hyperpolarizing factor (EDHF). Deficiency in CSE expression increases blood pressure in CSE knockout mice and significantly diminishes endothelium-dependent relaxation of resistance arteries. More extensive and mechanistic studies in the future will help to determine whether H2S is a new EDRF or the very EDHF.