Cl^– absorption and HCO₃^– secretion is the main function of the pancreatic duct. Cl^– absorption and HCO₃^– secretion is mediated by a concerted action of Cl^––HCO₃^– exchangers and CFTR at the luminal membrane of the duct. CFTR controls the entire process as evident from the absence of ductal Cl^– absorption and HCO₃^– secretion in CF, which results in destruction of the pancreas. The identity of the luminal Cl^––HCO₃^– exchangers was revealed with the identification of the SLC26 transporters. The exact exact function of CFTR and the SLC26 transporters in pancreatic duct Cl^– absorption and HCO₃^– secretion and the relationship between them is not well understood. We will present evidence that two of the SLC26 transporters, SLC26a3 and SLC26a6 function as electrogenic transporters with isoform specific stoichiometry. CFTR regulates the activity of both transporters and, in turn, they regulate the activity of CFTR. Furthermore, new data suggest that the two SLC26 transporters differentially regulate CFTR. Whereas SLC26a3 only activates CFTR, SLC26a6 inhibits the basal activity of CFTR but activates the forskolin-stimulated CFTR, both in expression systems and in vivo. The significance of this form of regulation to pancreatic duct Cl^– absorption and HCO₃^– secretion is being examined in the SLC26a6-/- mouse.