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⁻. The key transporters mediating acinar fluid and electrolyte secretion are the basolateral Na⁺/K⁺ /2Cl⁻ cotransporter, the luminal Ca²⁺-activated Cl⁻ channel ANO1 and basolateral and luminal Ca²⁺-activated K⁺ channels. 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. The function of these regulatory pathways in secretory glands acinar cells is yet to be examined. 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 as a third messenger that integrates and synergizes the function of the Ca²⁺ and cAMP signaling pathways in activation of epithelial fluid and electrolyte secretion. These concepts are discussed in this review using secretion by the pancreatic and salivary gland ducts as model systems.