The exocrine pancreas secretes HCO3−-rich fluid in response to secretin. The failure of adequate HCO3− and water secretion appears to be the primary defect in cystic fibrosis of the pancreas. We have, therefore, examined the mechanisms for HCO3− and water transport in isolated pancreatic ducts using microfluorometry. Most of the HCO3− uptake (∼75%) at the basolateral membrane of duct cells is conducted by the Na+-HCO3− co-transport (NBC) and the rest is by the Na+/H+ exchange (NHE). Water is transported via aquaporin 1 (AQP1) water channel following the osmotic gradient created by the active transport of Cl− and HCO3− via the cystic fibrosis transmembrane conductance regulator (CFTR). The immunohistochemical localizations of NBC, CFTR, and AQP1 in human and guinea pig pancreas were consistent with physiological findings. In pancreatic duct segments isolated from mice with delta F508 mutation (delta F), the osmotic water permeability (Pf) from homozygous (delta F/delta F) mice (405 ± 25 mm/s, n = 6) was significantly (p<0.01) higher than that from wild-type mice (166 ± 18 mm/s, n = 8). This suggests that the expression of aquaporin is up-regulated when CFTR function is abolished. [Jpn J Physiol 55 Suppl:S35 (2005)]