Observations from a variety of model systems suggest that ductular bile formation is mediated in large part by transepithelial transport of Cl-ions and have identified Cl-channels in the apical membrane as important targets for hormones and other factors that modulate bile volume and composition through effects on duct cells. Signaling through secretin receptors that stimulate adenylyl cyclase and activate the cystic fibrosis transmembrane regulator (CFTR) Cl-channels represents a prototype for cholangiocyte secretion. However, recent observations indicate that cholangiocytes also express a variety of receptors that modulate secretory responses in the absence of effects on cyclic adenosine monophosphate (cAMP), and Cl-channels unrelated to CFTR have been identified. Moreover, rapid exocytosis of subapical vesicles is coupled closely to different Cl-secretory responses. These observations suggest that the protein composition of the apical domain is regulated by selective exocytosis and endocytosis of channel-containing vesicles, leading to rapid modulation of the transport capacity of individual cells in response to changing physiologic demands.