On a typical Western diet, the body is faced with the generation of a metabolically derived acid load that must be excreted to maintain systemic acid-base balance. The kidney is responsible for this task and matches daily acid excretion with daily acid production. Multiple nephron segments are involved in the process, including the proximal tubule cell. This review discusses the acid-activated signaling pathway in the proximal tubule that senses a decrease in cell pH and then mediates stimulation of the apical membrane Na/H antiporter, isoform NHE3. NHE3 mediates secretion of the majority of protons involved in bicarbonate reclamation, is involved in ammonium secretion, and provides a source of luminal protons for titrating filtered titratable acids and secreted ammonia to ammonium.