Zn 2+ is an essential element for cell survival/growth, and its deficiency is linked to many disorders. Extracellular Zn 2+ concentration changes participate in modulating fundamental cellular processes such as proliferation, secretion, ion transport, and cell signal transduction in a mechanism that is not well understood. Here, we hypothesize that the Zn 2+-sensing receptor ZnR/G protein-coupled receptor 39 (GPR39), found in tissues where dynamic Zn 2+ homeostasis takes place, enables extracellular Zn 2+ to trigger intracellular signaling pathways regulating key cell functions in vascular cells. Thus, we investigated how extracellular Zn 2+ regulates cell viability, proliferation, motility, angiogenesis, vascular tone, and inflammation through ZnR/GPR39 in endothelial cells. Knockdown of GPR39 through siRNA largely abolished Zn 2+-triggered cellular activity changes, Ca 2+ responses, as well as the downstream activation of Gαq-PLC pathways. Extracellular Zn 2+ promoted vascular cell survival/growth through activation of cAMP and Akt as well as overexpressing of platelet-derived growth factor-α receptor and vascular endothelial growth factor A. It also enhanced cell adhesion and mobility, endothelial tubule formation, and cytoskeletal reorganization. Such effects from extracellular Zn 2+ were not observed in GPR39 −/− endothelial cells. Zn 2+ also regulated inflammation-related key molecules such as heme oxygenase-1, selectin L, IL-10, and platelet endothelial cell adhesion molecule 1, as well as vascular tone-related prostaglandin I2 synthase and nitric oxide synthase-3. In sum, extracellular Zn 2+ regulates endothelial cell activity in a ZnR/GPR39-dependent manner and through the downstream G αq-PLC pathways. Thus, ZnR/GPR39 may be a therapeutic target for regulating endothelial activity.