Secretory epithelial cells are found in exocrine organs such as the pancreas and are also found in the lining of the lungs and gut. One important regulator of cell function in epithelial cells is the concentration of cytosolic Ca2+. The study of Ca2+ signaling in these cells has a long history and recent work has now identified, at the molecular level, key components in the Ca2+ signaling cascade. Furthermore, advances in fluorescent imaging techniques has enabled a detailed insight into the subcellular distribution of the agonist-evoked [Ca2+]i signal. A number of spatially different [Ca2+]i responses have been identified. Firstly, global [Ca2+]i signals are observed in response to high agonist concentration. Secondly, at lower agonist concentrations trains of local [Ca2+]i spikes, restricted to the secretory pole region of pancreatic acinar cells, have been identified. Finally, these local [Ca2+]i spikes have now been further devolved into microdomains of [Ca2+], elevation. The [Ca2+]i signal within a single microdomain has been shown to be the crucial trigger in the regulation of the ion channels important in fluid secretion.