Cl^– absorption and HCO₃^– secretion are central functions of secretory epithelia. CFTR mediates and/or regulate these transport activities as evident from the aberrant Cl^– and HCO₃^– transport is cystic fibrosis (CF). However, the exact role of CFTR in Cl^– absorption and HCO₃^– secretion and its regulation are not well understood. In a previous work we showed that CFTR stimulates Cl^–-dependent HCO₃^– transport and this activity is aberrant in CFTR mutants associated with CF. The identity of the protein mediating HCO₃^– transport and the mechanism of this stimulation are obscure. Characterized net Cl^– and HCO₃^– fluxes and Cl^– and HCO₃^– currents in HEK293 cells and Xenopus oocytes expressing WT-CFTR show that the bulk of the CFTR-supported Cl^– and HCO₃^– transport are coupled. However, HCO₃^– current could not account for net CFTR-stimulated HCO₃^– transport. In search of this mechanism we found that CFTR does not regulate the activity of any of the anion exchangers, AE1, AE2, AE3 or AE4. By contrast, CFTR markedly activated Cl^– and HCO₃^– by all members of the luminal SLC26 transporters tested DRA, Pendrin and SLC26A6. Current and voltage measurements revealed that the all SLC26 transporters are electrogenic Cl^– and HCO₃^– transporters with isoform specific stoichiometry. DRA activity occurred at a stoichiometry of Cl^–/HCO₃^– ≥ 2. By contrast SLC26A6 activity occurred at stoichiometry of HCO₃^–/Cl^– ≥ 2. DRA/CLD activity was responsible for the Cl^– and HCO₃^– transport stimulated by CFTR, since mutations in DRA/CLD that are associated with congenital chloride diarrhoea (CLD) had no Cl^–/HCO₃^– exchange activity in either the presence or absence of CFTR. To identify domains in CFTR responsible for regulation of the SLC26 transporters the activity of ΔR-CFTR and ΔC-CFTR from which the PDZ ligand was deleted were examined. ΔR-CFTR was unable to activate DRA/CLD. ΔC-CFTR at low expression levels could not be co-immunoprecipitated with DRA/CLD or activate the transporter. However, at high expression levels ΔC-CFTR and ΔC-DRA interacted with each other and ΔC-CFTR activated Cl^– and HCO₃^– transport by ΔC-DRA, indicating multiple interacting domains between CFTR and the SLC26 transporters. These findings provide a molecular mechanism for epithelial HCO₃^– transport. Expression of one SLC26 transporter and its activation by CFTR will result in electrogenic transport, whereas expression of two SLC26 transporters with opposite stoichiometry in the same membrane domain will result in electroneutral transport. Furthermore, these findings are relevant to the CF-associated aberrant Cl^– and HCO₃^– transport, and reveal a new function of CFTR with implications for CF and congenital chloride diarrhoea.