Microvillus membrane vesicles isolated from renal cortex have subsequently served as a useful model system for characterizing the kinetic and biochemical features of a Na+–H+ exchanger whose properties are largely representative of plasma membrane Na+–H+ exchangers in general. This chapter reviews studies on the molecular properties of the renal microvillus membrane Na+–H+ exchanger. Additional transport systems for the transfer of acids or bases exist in parallel with the Na+–H+ exchanger on the luminal membrane of proximal tubule cells. The chapter describes the kinetics of the renal Na+–H+ exchanger. As the imidazolium ring of histidine is the principal ionic group in proteins that is titratable at near-neutral pH values, in the study described in the chapter, this helped to evaluate the effect of histidine-specific reagents on the activity of the renal microvillus membrane Na+–H+ exchanger. The carboxyl-activating reagent N-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline (EEDQ) inhibits Na+–H + exchange in renal microvillus vesicles. Also, The observations that N,N'-dicyclohexyl-carbodiimide (DCCD) inactivates the renal Na+–H+ exchanger irreversibly and that amiloride protects against this inactivation suggested a strategy for covalently labeling the transport protein or one of its subunits. The renal Na+–H+ exchanger helps in facilitating anion transport by HCO−3 reabsorption, organic anion reabsorption, Cl− reabsorption, and anion transport and maintaining intracellular pH.