This review focuses on the hypothesis that biliary HCOmath image secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to prevent the uncontrolled membrane permeation of protonated glycine-conjugated bile acids. Functional impairment of this biliary HCOmath image umbrella or its regulation may lead to enhanced vulnerability of cholangiocytes and periportal hepatocytes toward the attack of apolar hydrophobic bile acids. An intact interplay of hepatocellular and cholangiocellular adenosine triphosphate (ATP) secretion, ATP/P2Y- and bile salt/TGR5-mediated Cl/ HCOmath image exchange and HCOmath image secretion, and alkaline phosphatase–mediated ATP breakdown may guarantee a stable biliary HCOmath image umbrella under physiological conditions. Genetic and acquired functional defects leading to destabilization of the biliary HCOmath image umbrella may contribute to development and progression of various forms of fibrosing/sclerosing cholangitis. (HEPATOLOGY 2010)