Eukaryotic genomes code for at least eight medium-chain dehydrogenases/reductases (MDR) enzyme families of two types, with and without Zn2+ at the active site. Four families have Zn2+: 'Dimeric alcohol dehydrogenases (ADHs)' (including liver ADHs), 'Tetrameric ADHs' (including the yeast ADHs), 'Cinnamyl ADHs' and 'Polyol DHs'. In the human genome, there are minimally 23 MDR genes, but the list is still growing from further interpretations. Of these, seven genes on chromosome 4 (and three pseudogenes) represent the ADH classes in the gene order IV, I?, Iß, Ia, V, II and III. The lineages leading to human ADH establish five levels of divergence, with nodes at the MDR/short-chain dehydrogenases/reductases (SDR), dimer/tetramer, class III/non-III, further class, and intraclass levels of divergence. These multiplicities allow conclusions on pathways of function for ADHs and suggest this activity to have two roles in addition to its function in metabolism, one of a basic defence nature, the other of regulatory value in higher eukaryotes. © 2002 Elsevier Science Ireland Ltd. All rights reserved.