Epithelial cells are bound by a plasma membrane that is divided into apical and basolateral domains. In turn, the species of membrane proteins within these polarized plasmalemmal domains define the structural and functional specializations of the epithelium. Currently, research into the mechanisms whereby epithelial cell polarity is generated is a major thrust in cell biology. The topic discussed here will focus on recent studies carried out by us on the genesis of regulated secretion in the developing pancreatic acinar cell--that is, the secretory pathway responsive to second-messenger elevation after hormonal stimulation. In the developing rat pancreas, acinar cells complete cytodifferentiation 1 day before birth yet do not discharge secretory proteins from zymogen granules in response to the secretagogue cholecystokinin (CCK). The cause of this refractoriness to CCK does not lie at the receptor level, since the number, affinity, and plasmalemmal location of the receptor and its ability to generate second messengers after interaction with the ligand has already appeared. However, 1 day after birth, the acinar cell is able to discharge secretory proteins by exocytosis through the regulated secretory pathway in response to CCK. The acquisition of distal stimulus-secretion coupling events in the perinatal period has been found to correlate with developmental changes in Ca2+/calmodulin-dependent protein kinase II and its phosphorylated substrates. The relevance of the studies reported here to the complex and coexistent regulated and constitutive secretory pathways in the pancreatic acinar cell will be discussed.