Phenotypic variation in human drug metabolism frequently can be attributed to polymorphisms in genes that encode drug-metabolizing enzymes (DMEs). However, levels of Phase I and Phase II DMEs also vary because many of these enzymes are induced by a myriad of xenobiotic chemicals. Individual differences in the capacity for induction contribute to variation in drug metabolism in human populations. Induction is mediated by intracellular receptors that act as ligand-dependent transcription factors, including several members of the nuclear receptor (NR) superfamily and the aryl hydrocarbon receptor (AHR). Genetic variations (SNPs and others) exist in genes that encode these human receptors but few of the known polymorphisms have any significant effect on enzyme induction. We suggest that the current scarcity of SNPs that are able to alter function in the DME-regulating NRs reflects considerable evolutionary selective pressures that conserve the key functional domains in these receptors.