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Calcium (Ca²⁺) is a versatile second messenger that regulates a number of cellular processes in virtually every type of cell. The inositol 1,4,5-trisphosphate receptor (ITPR) is the only intracellular Ca²⁺ release channel in cholangiocytes, and is therefore responsible for Ca²⁺-mediated processes in these cells. This review will discuss the machinery responsible for Ca²⁺ signals in these cells, as well as experimental models used to investigate cholangiocyte Ca²⁺ signaling. We will also discuss the role of Ca²⁺ in the normal and abnormal regulation of secretion and apoptosis in cholangiocytes, two of the best characterized processes mediated by Ca²⁺ in this cell type.