Alcohol and tobacco are responsible for a very large proportion of chronic disease and some tumors in particular may be the result of interactions between the two risk factors. The present systematic literature review was conducted to judge combined effects of alcohol drinking and tobacco, as well as and genetic polymorphisms on alcohol-related cancer risk. We can conclude that the interaction of smoking and alcohol significantly increases the risk for aero-digestive cancers. Unfortunately, little is known about mechanisms and details of interaction with regard to disease outcomes, which is why particular questions must be targeted in future research efforts.