The activity of the hexose monophosphate (HMP) shunt dehydrogenases was measured in rat kidney homogenates under condi?tions of acid-base and electrolyte change, and in kidneys undergoing regeneration following unilateral nephrectomy. HMP shunt activity was markedly increased in kidneys from animals in NH4Cl acidosis. A significant positive correlation between HMP shunt enzymes and acid excretion was found (r = 0.74). The stimulus appeared to be intra-cellular rather than extracellular pH, since the enzymes increased both in metabolic acidosis and in hypokalemic alkalosis. Sodium deple?tion also enhanced the activity of HMP shunt enzymes and seemed to account for a small portion of the increase observed in acidosis. Dose-response and time-course studies of NH4Cl effect on HMP shunt enzymes, together with the statistically significant correlation with acid excretion, prompt the conclusion that such changes of HMP shunt activity form part of the renal response to acid-base imbalance. The possible functional significance of these phenomena is discussed.