Adenosine regulates the function of the innate and adaptive immune systems through targeting virtually every cell type that is involved in orchestrating an immune/inflammatory response. Of the four adenosine receptors (A1, A2A, A2B, A3), A2A receptor is the primary anti-inflammatory effectors of extracellular adenosine. A2A receptor predominant expresses in monocytes/macrophages, dendritic cells, mast cells, neutrophils, endothelial cells, eosinophils, epithelial cells, as well as lymphocytes, NK cells, and NKT cells. Its activation inhibits early and late events occurring during an immune response. A2A receptor also participates in tissue remodeling and reparation. A2A receptor has been shown to impact the course of a wide spectrum of ischemic, autoimmune, infectious, and allergic diseases, and has regulatory roles in immune/inflammatory diseases of various organs, including heart, lung, gut, liver, kidney, joints, and brain. Recently, A2A receptor has become a particularly attractive target to manage psychiatric disorders.