Emerging evidence suggests that perivascular adipose tissue (PVAT) has a relevant role in the control of vascular tone in physiology and pathology. Healthy PVAT has anticontractile, anti-inflammatory, and antioxidative actions. Accumulating data from both human and experimental animal models indicate that PVAT dysfunction is conceivably coupled to cardiovascular diseases, and it is associated with vascular inflammation, oxidative stress, and arterial remodeling. Therefore, "healthy" PVAT may constitute a novel therapeutic target for the prevention and treatment of cardiovascular diseases. Hydrogen sulfide (HS) has been recognized as a vascular anti-contractile factor released from PVAT. The enzymes deputed to HS biosynthesis are variously expressed in PVAT and strictly dependent on the vascular bed and species. Metabolic and cardiovascular diseases can alter the morphological and secretory characteristics of PVAT, influencing also the HS signaling. Here, we discuss the role of PVAT-derived HS in healthy conditions and its relevance in alterations occurring in vascular disorders. We discuss how a better understanding may help in the prevention of vascular dysfunction related to alteration in PVAT-released HS as well as the importance of the interplay between PVAT and HS. We propose future directions to evaluate the contribution of each enzyme involved in HS biosynthesis and their alteration/switch occurring in vascular disorders and the remaining challenges in investigating the role of HS. . 37, 84-97.