The nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) were cloned and/or established as xenobiotic receptors in 1998.Due to their activities in the transcriptional regulation of phase I and phase II enzymes as well as drug transporters,PXR and CAR have been defined as the master regulators of xenobiotic responses.The discovery of PXR and CAR provides the essential molecular basis by which drugs and other xenobiotic compounds regulate the expression of xenobiotic enzymes and transporters.This article is intended to provide a historical overview on the discovery of PXR and CAR as xenobiotic receptors. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) were cloned and / or established as xenobiotic receptors in 1998. Due to their activities in the transcriptional regulation of phase I and phase II enzymes as well as drug transporters, PXR and CAR have been defined as the master regulators of xenobiotic enzymes. The discovery of PXR and CAR provides the essential molecular basis by which drugs and other xenobiotic compounds regulate the expression of xenobiotic enzymes and transporters. This article is intended to provide a historical overview on the discovery of PXR and CAR as xenobiotic receptors.