Ethanol administration impairs multiple aspects in the process of receptor-mediated endocytosis (RME) in the liver. Studies from our laboratory over the last 10 years have carefully examined RME by the hepatocyte-specific asialoglycoprotein receptor (ASGP-R). We have identified a time course for ethanol-induced defects in RME and established that many of the impairments occur initially in the centrilobular region of the liver and as early as one week after ethanol administration. Impaired intravesicular acidification in ethanol-fed animals has been identified, and these defects in acidification could alter multiple protein trafficking pathways including RME. In addition to altered acidification, altered receptor function (including receptor inactivation) could also contribute to impaired trafficking. Current studies in our laboratory are aimed at an examination of posttranslational modifications in the receptor (acylation and phosphorylation) that are known to affect its function. A role for the ASGP-R in the process of alcoholic apoptosis is also being examined because proper functioning of the ASGP-R is thought to be important in clearance of apoptotic cells.