This review focuses on the regulation of the mammalian medium-chain alcohol dehydrogenase (ADH) genes. This family of genes encodes enzymes involved in the reversible oxidation of alcohols to aldehydes. Interest in these enzymes is increased because of their role in the metabolism of beverage alcohol as well as retinol, and their influence on the risk for alcoholism. There are six known classes ADH genes that evolved from a common ancestor. ADH genes differ in their patterns of expression: most are expressed in overlapping tissue-specific patterns, but class III ADH genes are expressed ubiquitously. All have proximal promoters with multiple cis-acting elements. These elements, and the transcription factors that can interact with them, are being defined. Subtle differences in sequence can affect affinity for these factors, and thereby influence the expression of the genes. This provides an interesting system in which to examine the evolution of tissue specificity. Among transcription factors that are important in multiple members of this gene family are the C/EBPs, Sp1,USF, and AP1, HNF-1, CTF/NF-1, glucocorticoid, and retinoic acid receptors, and several as-yet unidentified negative elements, are important in at least one of the genes. There is evidence that cis-acting elements located far from the proximal promoter are necessary for proper expression. Three of the genes have upstream AUGs in the 5' nontranslated regions of their mRNA, unusual for mammalian genes. The upstream AUGs have been shown to significantly affect expression of the human ADH5 gene.