The positioning of lymphocytes in immune organs and the migration of lymphocytes that occurs during normal immune surveillance and following immune activation depends on appropriate signaling through receptors that couple to heterotrimeric G-proteins. In addition other mediators that affect lymphocyte function, such as histamine, purine nucleosides, C5A, prostaglandins, leukotrienes, serotonin, epinephrine, opioids, and certain phospholipids, also signal through G-protein-coupled receptors (GPCRs). Downstream of heterotrimeric G-proteins are a limited number of downstream effectors, which, in turn, activate a large number of other signaling molecules, many of which are shared with other signaling pathways, such as those activated by antigen receptors, coreceptors, and adhesion receptors. Crucial to signaling through GPCRs are finely developed regulatory systems, which control the activation of heterotrimeric G-proteins and their interactions with their immediate downstream effectors. This review will focus on the overall importance of GPCR signaling in lymphocyte function and an upstream regulatory system present in lymphocytes, which fine tunes heterotrimeric G-protein signaling.