Although a major fraction of Cl⁻ reabsorption in the proximal tubule is passive and paracellular, there is an additional component of Cl⁻ transport that is transcellular. A search for possible mechanisms that might mediate Cl⁻ uptake into proximal tubule cells led to the identification of an apical membrane Cl--oxalate exchange activity. Subsequent studies identified anion transporter SLC26A6 as responsible for proximal tubule Cl⁻-oxalate exchange activity. The most striking phenotype in Slc26a6 null mice was calcium oxalate urolithiasis due to hyperoxaluria. Hyperoxalemia and hyperoxaluria in Slc26a6 null mice were found to be caused by defective intestinal back-secretion of ingested oxalate. These findings suggested that inherited or acquired defects in SLC26A6 might lead to hyperoxaluria and increased stone risk, and have motivated studies to characterize the role of SLC26A6 in oxalate homeostasis in patients and in animal models.