The physiological and biomedical importance of hydrogen sulfide (H2S) has been fully recognized in the cardiovascular system as well as in the rest of the body. In blood vessels, cystathionine γ-lyase (CSE) is a major H2S-producing enzyme expressed in both smooth muscle and endothelium as well as periadventitial adipose tissues. Regulation of H2S production from CSE is controlled by a complex integration of transcriptional, posttranscriptional, and posttranslational mechanisms in blood vessels. In smooth muscle cells, H2S regulates cell apoptosis, phenotypic switch, relaxation and contraction, and calcification. In endothelial cells, H2S controls cell proliferation, cellular senescence, oxidative stress, inflammation, etc. H2S interacts with nitric oxide and acts as an endothelium-derived relaxing factor and an endothelium-derived hyperpolarizing factor. H2S generated from periadventitial adipose tissues acts as an adipocyte-derived relaxing factor and modulates the vascular tone. Extensive evidence has demonstrated the beneficial roles of the CSE/H2S system in various blood vessel diseases, such as hypertension, atherosclerosis, and aortic aneurysm. The important roles signaling in the cardiovascular system merit further intensive and extensive investigation. H2S-releasing agents and CSE activators will find their great applications in the prevention and treatment of blood vessel-related disorders.