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Transcellular Cl and HCO3 transport is a vital function of secretory epithelia and exit across the luminal membrane is mediated by members of the SLC26 transporters in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) channel. Typically, secretory epithelia express several SLC26 transporters in the same tissue; however, how their specific function is determined in vivo is not known. In the present work we used the parotid gland duct which expressed Slc26a4 and Slc26a6 and the model systems of Slc26a4−/− and Slc26a6−/− mice to study the role and regulation of these SLC26 transporters. We examined the transport modes of SLC26A4 expressed in Xenopus oocytes and report that SLC26A4 functions as a coupled, electroneutral I/Cl, I/HCO3 and Cl/HCO3 exchanger with 1: 1 stoichiometry, with I as the preferred anion. In the duct, Slc26a4 is expressed in the luminal membrane and mainly mediates I secretion with minimal role in luminal HCO3 transport. By contrast, Slc26a6 mediates luminal Cl/HCO3 exchange activity with minimal role in I secretion. Furthermore, silencing of CFTR altered Cl/HCO3 exchange by Slc26a6, but had no effect on I secretion by Slc26a4. Accordingly, deletion of Slc26a6, but not deletion of Slc26a4, results in dysregulation of CFTR. These findings provide the first evidence for a selective role of the SLC26 transporters expressed in the same tissue in epithelial anion transport and suggest that transport specificity is achieved by both the properties of the transporters and the composition of the complexes they form.