Fluid and HCO₃⁻ secretion is a vital function of all epithelia and is required for the survival of the tissue. Aberrant fluid and HCO₃⁻ secretion is associated with many epithelial diseases, such as cystic fibrosis, pancreatitis, Sjögren's syndrome, and other epithelial inflammatory and autoimmune diseases. Significant progress has been made over the last 20 years in our understanding of epithelial fluid and HCO₃⁻ secretion, in particular by secretory glands. Fluid and HCO₃⁻ secretion by secretory glands is a two-step process. Acinar cells secrete isotonic fluid in which the major salt is NaCl. Subsequently, the duct modifies the volume and electrolyte composition of the fluid to absorb the Cl⁻ and secrete HCO₃⁻. The relative volume secreted by acinar and duct cells and modification of electrolyte composition of the secreted fluids varies among secretory glands to meet their physiological functions. In the pancreas, acinar cells secrete a small amount of NaCl-rich fluid, while the duct absorbs the Cl⁻ and secretes HCO₃⁻ and the bulk of the fluid in the pancreatic juice. Fluid secretion appears to be driven by active HCO₃⁻ secretion. In the salivary glands, acinar cells secrete the bulk of the fluid in the saliva that is driven by active Cl⁻ secretion and contains high concentrations of Na⁺ and Cl⁻. The salivary glands duct absorbs both the Na⁺ and Cl⁻ and secretes K⁺ and HCO₃⁻. In this review, we focus on the molecular mechanism of fluid and HCO₃⁻ secretion by the pancreas and salivary glands, to highlight the similarities of the fundamental mechanisms of acinar and duct cell functions, and to point out the differences to meet gland-specific secretions.