Cytosolic Ca2+ signals are crucial for the control of fluid and enzyme secretion from exocrine glands. The highly polarized exocrine acinar cells have evolved sophisticated and complex Ca2+ signaling mechanisms that exercise precise control of the secretory events occurring across the apical plasma membrane bordering the gland lumen. Ca2+ stores in the endoplasmic reticulum, the secretory granules, the lysosomes, and the endosomes all play important roles in the generation of the local apical Ca2+ spikes that switch on Cl(-) channels in the apical plasma membrane as well as exocytotic export of enzymes. The mitochondria are crucial not only for ATP generation but also for the physiologically important subcellular compartmentalization of the cytosolic Ca2+ signals.