Exocrine cells of the digestive system are specialized to secrete protein and fluid in response to neuronal and/or hormonal input. Although morphologically similar, parotid and pancreatic acinar cells exhibit important functional divergence in their Ca²⁺ signaling properties. To address whether there may be fundamental differences in the exocytotic release of digestive enzyme from exocrine cells of the salivary gland versus the pancreas, we applied electrophysiological and optical methods to investigate the spatial and temporal characteristics of zymogen-containing secretory granule fusion at the single acinar cell level by direct or agonist-induced elevation of Ca²⁺ and cAMP. Temporally-resolved membrane capacitance measurements revealed that two apparent phases of exocytosis were induced by Ca²⁺ elevation: a rapidly activated initial phase that could not be resolved as individual fusion events and a second phase that was activated after a delay, increased in a staircase-like fashion, was augmented by cAMP elevation and likely reflected both sequential compound and multivesicular fusion of zymogen-containing granules. Optical measurements of exocytosis using time-differential imaging analysis revealed that zymogen granule fusion was induced following a minimum delay of ~200 ms, occurred initially at the apical and basolateral borders of acinar cells, and under strong stimulation proceeded from apical pole to deeper regions of the cell interior. Zymogen granule fusions appeared to coordinate subsequent fusions and produced persistent structures that generally lasted several minutes. In addition, parotid gland slices were used to assess secretory dynamics in a more physiological context. Parotid acinar cells were shown to exhibit both similar and divergent properties in comparison to the more well-studied pancreatic acinar cell regarding the spatial organization and kinetics of exocytotic fusion of zymogen granules.