Blood pH is maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. The molecular mechanisms involved in pH homeostasis are not completely understood. Acid-sensing ion channels are activated at relatively low pH (below 6.5), their setpoint is different from normal plasma pH. We have identified a family of G protein-coupled receptors that have proton-sensing properties, and show halfmaximal activation at pH 7.2-7.4. These receptors are ovarian cancer G protein-coupled receptor 1 (OGR1 aka GPR68), GPR4, and T cell death-associated gene 8 (TDAG8 aka GPR65). These membrane proteins had been originally described as receptors for bioactive lipids, however, these findings were later retracted. OGR1 is expressed in bone, kidney, and the vasculature. Recent data suggest that this receptor regulates acidosis-induced bone resorption, calcium secretion in the kidney, and vascular tone. GPR4 shows a rather specific expression in endothelial cells and modulates angiogenesis. TDAG8 is restricted to the immune system. Its role in the control of inflammatory processes is being explored. Pharmacological modulation of these proton-sensing GPCRs may have therapeutic potential for the treatment of immune disorders and cancer.