Alcohol and tobacco are frequently co-abused. Increased alcohol use and alcoholism are associated with smoking, and vice versa. Functional and/or metabolic cross-tolerance may contribute to this occurrence. This review summarizes recent studies published from our laboratory focusing on metabolic aspects of tolerance, which demonstrate that in rat, subchronic, behaviourally relevant doses of ethanol induce hepatic nicotine-metabolizing cytochrome P450 (CYP) 2B1, and that subchronically administered nicotine, at behaviourally relevant doses, induces hepatic ethanol-metabolizing CYP2E1. Increased CYP2B1 protein, mRNA and CYP2B1-mediated nicotine metabolism was observed following ethanol treatments. CYP2E1 protein and activity were induced by nicotine, but no changes were seen in levels of CYP2E1 mRNA. These data indicate that metabolic cross-tolerance may occur between nicotine and ethanol, suggesting that nicotine use may increase the elimination of ethanol, and ethanol use may increase the elimination of nicotine. Other implications, such as altered pharmacology and toxicology of drugs metabolized by these enzymes, as well as changes in pro-carcinogen and pro-toxin activation are also discussed.