Aberrant HCO3− transport is a hallmark of cystic fibrosis (CF) and is associated with aberrant Cl−-dependent HCO3− transport by the cystic fibrosis transmembrane conductance regulator (CFTR). We show here that HCO3− current by CFTR cannot account for CFTR-activated HCO3− transport and that CFTR does not activate AE1–AE4. In contrast, CFTR markedly activates Cl− and OH−/HCO3− transport by members of the SLC26 family DRA, SLC26A6 and pendrin. Most notably, the SLC26s are electrogenic transporters with isoform-specific stoichiometries. DRA activity occurred at a Cl−/HCO3− ratio ≥2. SLC26A6 activity is voltage regulated and occurred at HCO3−/Cl− ≥2. The physiological significance of these findings is demonstrated by interaction of CFTR and DRA in the mouse pancreas and an altered activation of DRA by the R117H and G551D mutants of CFTR. These findings provide a molecular mechanism for epithelial HCO3− transport (one SLC26 transporter—electrogenic transport; two SLC26 transporters with opposite stoichiometry in the same membrane domain—electroneutral transport), the CF-associated aberrant HCO3− transport, and reveal a new function of CFTR with clinical implications for CF and congenital chloride diarrhea.