Ethanol administration disorders protein trafficking in the liver. The protein secretory and plasma membrane assembly pathways have been shown to be impaired in the liver of ethanol-treated animals; however, traffic along the receptor-mediated endocytosis (RME) pathway appears to be especially susceptible to alterations by ethanol. Using asialoglycoproteins as model ligands for studying RME, we have identified at least three steps of this multi-step pathway that are affected by ethanol treatment. These altered steps are recycling of the receptor, internalization of the receptor-ligand complex and dissociation of the ligand from its receptor in endosomes. Ethanol-induced derangements of RME are more severe in the perivenule region, where alcoholic liver injury starts and predominates, than in the periportal region of the liver. Recent studies have shown that the endocytosis of other ligands, including epidermal growth factor and insulin, is also altered by ethanol treatment. Mechanisms which have been proposed to explain faulty RME include: acetaldehyde adducts to tubulin resulting in impaired microtubule function, improper acidification of endosomes and defective receptor clustering in coated pits. Since RME represents an important process by which levels of various hormones, growth factors and other ligands are regulated, and since RME may also be an integral process by which the biological effects of various ligands are elicited, changes in this important process could disrupt numerous metabolic and homeostatic events in the liver.