A P450 gene nomenclature system has recently been proposed on the basis of divergent evolution of distinct families and subfamilies among eukaryotes and prokaryotes. At present, eleven gene families have been described, eight of which exist in all mammals. The current number of P450 genes in each species is believed to reflect, at least in part, selective advantages as animals and plants have struggled for coexistence during the last 1 billion years. It is likely that P450 genes will also be found in archaebacteria, as well as most or all eubacteria and eukaryotes. Using Wu-Kabat analysis, we propose regions of the P450 protein involved in membrane attachment, flavoprotein-binding, heme-binding, and substrate specificity. The invariant amino acid sequence (F**G***C*G in the heme-binding region) is unique to the fifty P450 proteins characterized to date and is not found in any of the more than 5,430 other proteins presently in the database. The regulatory trans-acting protein factors and their associated upstream cis-acting DNA elements of the orthologous mouse, rat and human P450A1 gene are complex but appear to be highly conserved during the 80 million years since the mammalian radiation.