This essay presents a clinical model of the role of genetic factors in alcohol dependence. Data supporting a strong impact of environmental influences along with genetic heterogeneity and the absence of simple Mendelian models combine to produce a complex situation. In light of these complications, this essay presents a model developed by the author's research group focusing on the decreased reaction to alcohol as an important risk factor. The biological contributors might be polygenic or dominant with incomplete penetrance and must interact with environment. The application of this approach to other risk factors is set forth.