Most of the Na+ , Cl- and HCO3 - filtered by the kidney is reabsorbed in the proximal tubule. Several lines of evidence indicate that NHE3 is the principal Na+-H+ exchanger isoform involved in mediating acid secretion across the apical membrane. NHE8 is a newly identified isoform also expressed on the brush border in the proximal tubule, but its function remains unknown. A significant fraction of Cl - is reabsorbed via apical membrane Cl- -base exchange: Cl--formate exchange in parallel with Na+-H+ exchange and H+-formate cotransport, and Cl--oxalate exchange in parallel with oxalate-sulfate exchange and Na+-sulfate cotransport. Apical membrane Cl --OH-/HCO3-exchange has also been observed. SLC26 family members have emerged as candidates to mediate proximal tubule Cl--base exchange. Pendrin (SLC26A4) expression is not detected in the proximal tubule, and there is no change in transtubular NaCl absorption in pendrin null mice. In contrast, SLC26A6 (CFEX, PAT1) is expressed on the brush border of proximal tubule cells. Functional expression studies indicate that SLC26A6 is capable of mediating all of the modes of Cl--base exchange described to take place across the brush border membrane. In SLC26A6 null mice the effects of formate or oxalate to stimulate NaCl absorption in microperfused proximal tubules are reduced or absent, respectively, but there is no change in baseline NaCl absorption measured in the absence of formate and oxalate. These findings suggest that SLC26A6 primarily mediates proximal tubule Cl- absorption by Cl--oxalate exchange and Cl--formate exchange rather than by Cl--HCO3- or Cl--OH-exchange. Differential regulation of Cl--base exchange mediated by SLC26A6, and Na+-H+ exchange mediated by NHE3, may act as a switch to govern the ratio of transcellular NaHCO3 to NaCl reabsorption in the proximal tubule.