In the vascular wall, hydrogen sulfide (H 2 S) inhibits inflammation, stimulates angiogenesis, and activates vasodilation. There are multiple sources of H 2 S in the vascular wall, but cystathionine gamma-lyase (CSE) within endothelial cells appears to produce most of the local, vascular H 2 S. Generated H 2 S acts on smooth muscle, endothelial, inflammatory, and adipose cells within the vascular wall and contributes to circulating levels of H 2 S and H 2 S metabolites. H 2 S signaling is generally beneficial with evidence that it inhibits inflammation and protects cells from oxidative stress. H 2 S also stimulates vasodilation and suppresses cytokine generation. Oxidized low-density lipoproteins (oxLDL) and hyperglycemia downregulate the pathway in cultured cells and disease states. Lower plasma and urine levels have been reported in human studies of diabetes, hypertension, and atherosclerosis so that suppression of this system may contribute to vascular disease. Activation of the system or supplementation with exogenous donors of H 2 S appears to protect from vascular and inflammatory diseases. Areas of active research include delineating signal transduction pathways both upstream of CSE and downstream of released H 2 S as well as defining more accurate and user-friendly ways to measure endogenous production.