Neurotransmitter-regulation of fluid secretion in the salivary glands is achieved by a coordinated sequence of intracellular signaling events, including the activation of membrane receptors, generation of the intracellular second messenger, inositol 1,4,5, trisphosphate, internal Ca²⁺ release, and Ca²⁺ influx. The resulting increase in cytosolic [Ca²⁺ ] ([Ca²⁺]_i) regulates a number of ion transporters, e.g., Ca²⁺-activated K+ channel, Na⁺/K⁺/2Cl ^- co-transporter in the basolateral membrane, and the Ca2+-activated Cl^- channel in the luminal membrane, which are intricately involved in fluid secretion. Thus, regulation of [Ca²⁺]_i is central to the regulation of salivary acinar cell function and is achieved by the concerted activities of several ion channels and Ca²⁺-pumps localized in various cellular membranes. Ca2+ pumps, present in the endoplasmic reticulum and the plasma membrane, serve to remove Ca²⁺ from the cytosol. Ca2+ channels present in the endoplasmic reticulum and the plasma membrane facilitate rapid influx of Ca²⁺ into the cytosol from the internal Ca²⁺ stores and from the external medium, respectively. It is well-established that prolonged fluid secretion is regulated via a sustained elevation in [Ca²⁺]_i that is primarily achieved by the influx of Ca²⁺ into the cell from the external medium. This Ca²⁺ influx occurs via a putative plasma-membrane-store-operated Ca²⁺ channel which has not yet been identified in any non-excitable cell type. Understanding the molecular nature of this Ca2+ influx mechanism is critical to our understanding of Ca²⁺ signaling in salivary gland cells. This review focuses on the various active and passive Ca ²⁺ transport mechanisms in salivary gland cells-their localization, regulation, and role in neurotransmitter-regulation of fluid secretion. In addition to a historical perspective of Ca²⁺ signaling, recent findings and challenging problems facing this field are highlighted.