Using protein and enzymatic methods, a major role in ethanol metabolism was assigned to the alcohol dehydrogenase (ADH) enzymes. Three major classes of ADHs were described on the basis of structure and function, including timing and location of expression. Polymorphic variants, including a common functional variant, were identified. Molecular cloning allowed the demonstration of a high degree of sequence homology between the three class I ADH genes and enabled the definition of ADH variants at the DNA sequence level. The existence of an ADH gene cluster on chromosome 4 and the shared evolutionary roots of these genes suggests that the continued integration of studies of the different ADH genes will yield further insights into alcohol metabolism in humans.