A central function of epithelia is the control of the volume and electrolyte composition of bodily fluids through vectorial transport of electrolytes and the obligatory H2O. In exocrine glands, fluid and electrolyte secretion is carried out by both acinar and duct cells, with the portion of fluid secreted by each cell type varying among glands. All acinar cells secrete isotonic, plasma-like fluid, while the duct determines the final electrolyte composition of the fluid by absorbing most of the Cl- and secreting HCO3 -. Ductal fluid and HCO3 – secretion are mediated by the basolateral membrane Na+-HCO3 – cotransporter NBCe1-B and the luminal membrane Cl-/HCO3 – exchanger slc26a6 and the Cl- channel CFTR. The function of the transporters is regulated by multiple inputs, which in the duct include major regulation by the WNK/SPAK pathway that inhibit secretion and the IRBIT/PP1 pathway that antagonize the effects of the WNK/SPAK pathway to both stimulate and coordinate the secretion. An important concept in biology is synergism among signaling pathways to generate the final physiological response that ensures regulation with high fidelity and guards against cell toxicity. While synergism is observed in all epithelial functions, the molecular mechanism mediating the synergism is not known. Recent work reveals a central role for IRBIT that integrates and synergizes the function of the Ca2+ and cAMP signaling pathways in activation of epithelial fluid and electrolyte secretion. In the resting state IRBIT is sequestered by the high level of IP3Rs at the apical pole. Minimal stimulation of Gs-coupled cAMP generating receptors results in PKA-mediated phosphorylation of the IP3Rs at specific serine residues that increases the apparent affinity of the IP3Rs to IP3 and at the same time reduces their apparent affinity to IRBIT. Now, weak stimulation of Gq-coupled GPCRs that generates minimal amount of IP3 results in dissociation of IRBIT from the IP3Rs and its translocation to CFTR and slc26a6 to activate them and stimulate fluid and electrolyte secretion. These findings provide a general molecular pathway for synergism between the Ca2+ and cAMP signaling pathways with multiple implications to disease states, including the autoimmune disease Sjogren’s syndrome and cystic fibrosis.