HCO3--rich fluid in the pancreatic juice (2 similar to 3 L/day) is secreted by epithelial cells lining the pancreatic duct tree, while digestive enzymes are secreted by acinar cells with a small amount of Cl--rich fluid. Ductal HCO3- secretion is not only regulated by gastrointestinal hormones and cholinergic nerves but is also influenced by luminal factors: intraductal pressure, Ca2+ concentration, pathological activation of protease and bile reflux. The maximum HCO3- concentration of the juice under secretin stimulation reaches 140-150 mM. Thus pancreatic duct cells secrete HCO3- against a similar to 7-fold concentration gradient. HCO3- secretion critically depends on the activity of CFTR, a cAMP-dependent anion channel localized in the apical membrane of various epithelia. In the proximal part of pancreatic ducts close to acinar cells HCO3- secretion across the apical membrane is largely mediated by SLC26A6 Cl--HCO3- exchanger. In distal ducts where the luminal HCO3- concentration is already high, most of the HCO3- secretion is mediated by HCO3- conductance of CFTR. CFTR is the causative gene for cystic fibrosis. Loss of function due to severe mutations in both alleles causes typical cystic fibrosis characterized by dehydrated, thick, and viscous luminal fluid/mucus in the respiratory and gastrointestinal tract, pancreatic duct, and vas deferens. A compound heterozygote of mutations/polymorphisms (causing a mild dysfunction of CFTR) involves a risk of developing CFTR-related diseases such as chronic pancreatitis. In cystic fibrosis and certain cases of chronic pancreatitis, the pancreatic duct epithelium secretes a small amount of fluid with neutral similar to acidic pH, which causes an obstruction of the duct lumen by a protein plug or viscous mucus.