Physiological stimulants generating cytosolic [Ca²⁺] elevations by release from internal stores utilize a variety of second messengers (IP3, cADPR and NAADP) to induce specific Ca²⁺ signal patterns [Petersen Cell Calcium 38, 171-200, 2005]. The Ca²⁺-releasing intracellular stores include the endoplasmic reticulum (ER), secretory granules, lysosomes and endosomes [Gerasimenko et al J Cell Sci 119, 226-38, 2006; Menteyne et al Curr Biol 16, 1931-7, 2006]. The agonist-specific Ca²⁺ signal patterns [Petersen et al EMBO J 10, 527-33, 1991] can be explained by differential and combinatorial coupling between various messengers and stores [Cancela et al EMBO J 21, 909-19, 2002; Menteyne et al Curr Biol 16, 1931-7, 2006]. Physiological Ca²⁺ signals are mostly local and oscillatory, but pathological insults cause sustained and global elevations of the cytosolic [Ca²⁺]. In pancreatic acinar cells, Ca²⁺ homeostasis is disrupted by hyperstimulation or toxins (bile acids and non-oxidative ethanol metabolites). Both the ER and acid stores become depleted of Ca²⁺, causing necrosis. Mitochondrial inhibition paralyses energy-dependent Ca²⁺ pumps causing cytosolic Ca²⁺ overload [Criddle et al Gastroenterology 130, 781-93, 2006] and digestive enzymes (proteases) are activated within post-exocytotic endocytic vacuoles [Sherwood et al PNAS 104, 5674-9, 2007]. When the stress applied to the cell is milder (generation of reactive oxygen species by the oxidant menadione) release of Ca²⁺ from stores leads to oscillatory global Ca²⁺ waves, associated with partial mitochondrial depolarization. This causes apoptosis [Criddle et al J Biol Chem 281, 40485-92, 2006].