The basic characteristics of cellular Ca²⁺ signaling will be reviewed with particular emphasis on events in the pancreatic acinar cells. Physiological stimulants of pancreatic exocrine secretion, such as cholecystokinin and acetylcholine, utilise up to 4 intracellular messengers (IP3, cADPR, NAADP and Ca²⁺ [Ca²⁺-induced Ca²⁺ release]) to induce specific oscillatory patterns of cytosolic Ca²⁺ signals in the acinar cells. These are tightly controlled in a temporal-spatial manner and are coupled to mitochondrial metabolism necessary to fuel secretion. The physiological Ca²⁺ signals controlling fluid and enzyme secretion are repetitive local (apical pole) and short- lasting (a few seconds) events. The Ca²⁺ signals are primarily generated by release of very small amounts of Ca²⁺ from up to 4 intracellular stores, namely the endoplasmic reticulum, the secretory granules, the lysosomes and the endosomes. These stores form an effective apical Ca²⁺ signaling complex. When normal Ca²⁺ homeostasis is disrupted by hyperstimulation or by toxic agents (for example, bile acids or non-oxidative ethanol metabolites - substances known to precipitate acute pancreatitis) Ca²⁺ stores become depleted and sustained cytosolic [Ca²⁺] elevations replace transient signals, leading to severe consequences. ATP depletion, due to mitochondrial inhibition, paralyses energy-dependent Ca²⁺ pumps causing cytosolic Ca²⁺ overload, whilst digestive enzymes are activated prematurely within post-exocytotic, endocytic vacuoles. The result is Ca²⁺-dependent cellular necrosis. However, when the stress applied to the acinar cell is relatively mild, release of Ca²⁺ from stores leads to oscillatory global waves, associated with partial mitochondrial depolarisation, and the result is apoptotic cell death.