Epithelial cells possess two plasma membrane domains, apical and basolateral, separated by tight junctions (TJs). Two principal pathways exist for the targeting of plasma membrane proteins: in the 'direct' pathway, proteins are sorted in the Golgi apparatus, possibly by clustering into or exclusion from glycosphingolipid-rich membrane microdomains (rafts, step 1). Transport vesicles destined for the apical and basolateral membranes bud from the trans Golgi network (TGN), in a process probably mediated by coat proteins (step 2). Vesicles are transported directionally along microtubules (MTs) or other cytoskeletal elements using vesicle-associated motors (step 3). After reaching the surface, vesicles dock and fuse utilizing the SNARE machinery at the basolateral and possibly also at the apical surface (step 4, see text for explanations). In the 'indirect' pathway, newly synthesized membrane proteins are first transported from the TGN to the basolateral surface and are then endocytosed into basolateral early endosomes (BEE). From here, apical proteins are transported along microtubules to the tubulovesicular 'apical recycling compartment' (ARC), which also receives proteins internalized from the apical surface. The final transport step to the apical plasma membrane involves the SNARE machinery since it is NSF-dependent and sensitive to botulinum toxin E (BotTx-E) which cleaves certain t-SNAREs.