Cytosolic Ca2+ is an important second messenger in virtually every type of cell. Moreover, Ca2+ generally regulates multiple activities within individual cells. This article reviews the cellular machinery that is responsible for Ca2+ signaling in cholangiocytes. In addition, two Ca2+-medi-ated events in cholangiocytes are discussed: bicarbonate secretion and apoptosis. Finally, emerging evidence is reviewed that Ca2+ signaling is involved in the pathogen-esis of diseases affecting the biliary tree and that Ca2+ signaling pathways can be manipulated to therapeutic advantage in the treatment of cholestatic disorders. Cytosolic Ca2 + is an important second messenger in virtually every type of cell. Moreover, Ca2 + generally regulates multiple activities within individual cells. This article reviews the cellular machinery that is responsible for Ca2 + signaling in cholangiocytes. In addition, two Ca2 + -medi-ated events in cholangiocytes are discussed: bicarbonate secretion and apoptosis. Finally, emerging evidence is that that Ca2 + signaling is involved in the pathogen-esis of diseases affecting the biliary tree and that Ca2 + signaling pathways can be manipulated to therapeutic advantage in the treatment of cholestatic disorders.