Ca²⁺ is a universal intracellular messenger that controls a wide range of cellular processes. In pancreatic acinar cells, acetylcholine and cholecystokinin regulate secretion via generation of repetitive local cytosolic Ca²⁺ signals in the apical pole. Bile acids and non-oxidative alcohol metabolites can elicit abnormal cytosolic Ca²⁺ signals that are global and sustained and result in necrosis. Necrosis results from excessive loss of Ca²⁺ from the endoplasmic reticulum, which is mediated by Ca²⁺ release through specific channels and inhibition of Ca²⁺ pumps in intracellular stores, followed by entry of extracellular Ca²⁺. Reduction of the cellular ATP level has a major role in this process. These abnormal Ca²⁺ signals, which can be inhibited by caffeine, explain how excessive alcohol intake and biliary disease cause acute pancreatitis, an often-fatal human disease in which the pancreas digests itself and its surroundings.