Maintenance of metabolic alkalosis generated by chloride depletion is often attributed to volume contraction. In balance and clearance studies in rats and humans, we showed that chloride repletion in the face of persisting alkali loading, volume contraction, and potassium and sodium depletion completely corrects alkalosis by a renal mechanism. Nephron segment studies strongly suggest the corrective response is orchestrated in the collecting duct, which has several transporters integral to acid-base regulation, the most important of which is pendrin, a luminal Cl/HCO(3)(-) exchanger. Chloride depletion alkalosis should replace the notion of contraction alkalosis.