The exocrine pancreas is comprised of three prominent cell types. While the roles of the acinar and ductal cells in physiology and disease are reasonably well defined, a third cell type, the pancreatic stellate cell (PSC) is far less studied. PSC are present in a periacinar and periductal localization. In common with hepatic stellate cells they are characterized as retinol/lipid storing cells expressing a variety of intermediate filament proteins including desmin and glial fibrillary acid protein. Under physiological conditions, stellate cells appear to be quiescent and relatively little is known regarding their contribution to the normal function of the gland. However, in culture, PSC undergo a phenotypic transformation from a quiescent state to a myofibroblast-like phenotype. This is believed to parallel the induction of an activated state observed in chronic pancreatitis and pancreatic cancer. Activated PSCs are highly proliferative, migratory and secrete large amounts of extracellular matrix. These properties are thought to contribute to the pathogenesis of pancreatic disease. The goal of the present study was to define the role of changes in intracellular Calcium concentration ([Ca2+]i) in mouse PSC function. We have utilized a variety of techniques, including pharmacological agents and adenoviral constructs which buffer [Ca2+] and Inositol 1,4,5-trisphosphate in specific cellular compartments and used these approaches to probe the contribution of Ca2+ release and Ca2+ influx for PSC function. For example, data will be presented which suggests that Ca2+ signaling does not appear to play a major role in the activation of quiescent PSC. Nevertheless, following activation, an increase in [Ca2+] within the nucleus is required for proliferation. This appears to be dependent on Ca2+ release, because blockade of Ca2+ influx is without effect on growth. In contrast, migration of activated stellate cells is attenuated in the absence of Ca2+ influx. These data suggest that Ca2+ signaling plays multiple roles in PSC function and further that manipulation of this signal may be a promising future target for clinical intervention.