Drug-metabolizing enzymes, including phase II conjugating enzymes, play an important role in both drug metabolism and human diseases. The genes that encode these enzymes and transporters are inducible by numerous xenobiotics and endobiotics and the inducibility shows clear species specificity. In the past several years, orphan nuclear receptors, such as PXR and CAR, have been established as species-specific "xenobiotic receptors" that regulate the expression of phase I and phase II enzymes and drug transporters. The creation of xenobiotic receptor transgenic and knockout mice has not only provided an opportunity to dissect the transcriptional control of drug metabolizing enzymes, but also offered a unique opportunity to study the xenobiotic receptor-mediated enzyme regulation in both drug metabolism and diseases. "Humanized" hPXR transgenic mice represent a major step forward in the creation and utilization of humanized rodent models for toxicological assessment that may aid in the development of safer drugs.