Regulation of blood pH—critical for virtually every facet of life—requires that the renal proximal tubule (PT) adjust its rate of H⁺ secretion (nearly the same as the rate of HCO₃^– reabsorption, J_HCO3) in response to changes in blood [CO₂] and [HCO₃^–]. Yet CO₂/HCO₃^– sensing mechanisms remain poorly characterized. Because receptor tyrosine kinase inhibitors render J_HCO3 in the PT insensitive to changes in CO₂ concentration, we hypothesized that the structural features of receptor protein tyrosine phosphatase- (RPTP) that are consistent with binding of extracellular CO₂ or HCO₃^– facilitate monitoring of blood CO₂/HCO₃^– concentrations. We now report that PTs express RPTP on blood-facing membranes. Moreover, RPTP deletion in mice eliminated the CO₂ and HCO₃^– sensitivities of J_HCO3 as well as the normal defense of blood pH during whole-body acidosis. Thus, RPTP appears to be a novel extracellular CO₂/HCO₃^– sensor critical for pH homeostasis.