The secretion of fluid and electrolytes by salivary gland acinar cells requires the coordinated regulation of multiple water and ion transporter and channel proteins. Notably, all the key transporter and channel proteins in this process appear to be activated, or are up-regulated, by an increase in the intracellular Ca2+ concentration ([Ca2+]i). Consequently, salivation occurs in response to agonists that generate an increase in [Ca2+]i. The mechanisms that act to modulate these increases in [Ca2+]i obviously influence the secretion of salivary fluid. Such modulation may involve effects on mechanisms of both Ca2+ release and Ca2+ entry and the resulting spatial and temporal aspects of the [Ca2+]i signal, as well as interactions with other signaling pathways in the cells. The molecular cloning of many of the transporter and regulatory molecules involved in fluid and electrolyte secretion has yielded a better understanding of this process at the cellular level. The subsequent characterization of mice with null mutations in many of these genes has demonstrated the physiological roles of individual proteins. This review focuses on recent developments in determining the molecular identification of the proteins that regulate the fluid secretion process.