The role of acid Ca²⁺ pools in both physiology and pathophysiology has been controversial, but much evidence has recently accumulated indicating that these pools are functionally important for cellular regulation. The pancreatic acinar cell, which is a classical object for Ca²⁺ signalling studies provides a good example. High-resolution confocal and two-photon studies of the dynamics of [Ca²⁺] in the cytosol and the major organelles have shown that physiological stimuli (acetylcholine and cholecystokinin) elicit repetitive release of tiny quantities of Ca²⁺ from the endoplasmic reticulum (ER) resulting in spiking Ca²⁺ signal patterns in the apical part of the cytosol, driving fluid and enzyme secretion (Petersen & Tepikin Annu Rev Physiol 70, 273–299, 2008). In contrast, pathological stimuli (alcohol/alcohol metabolites/bile acids) initiating the human disease acute pancreatitis, generate sustained, global and toxic elevations of the cytosolic [Ca²⁺] due to massive release of Ca²⁺ from both the ER and acid stores (Petersen et al Cell Calcium 45, 634–642, 2009; Petersen et al Cell Calcium in press 2011). It is the excessive Ca²⁺ release from the acid stores, rather than from the ER, that activates intracellular proteases leading to auto-digestion. The Ca²⁺ release from the acid stores occurs principally via IP3 receptors of sub-types 2 and 3 (Gerasimenko et al PNAS 106, 10758–10763, 2009). Very recently we have discovered that intracellular calmodulin has a protective effect against toxic Ca²⁺ signal generation and the resulting intracellular protease activation. We have also shown that this protective effect can be boosted significantly by application of a membrane-permeable Ca²⁺-like peptide (Gerasimenko et al PNAS 108, 5873–5878, 2011).