We recently cloned the human, rabbit, rat, and mouse orthologs of a novel member of the steroid/retinoid/thyroid hormone receptor family, which we have named the Pregnane X Receptor (PXRs). The discovery and characterization of PXR has led to an increased understanding of the molecular basis of many drug-drug interactions as well as a better understanding of xenobiotic metabolism in general. The key insights into PXR action was the finding that this nuclear receptor is linked to regulation of the cytochrome P450 3A monooxygenase (CYP3A) genes. Several lines of evidence indicate that PXR mediates the induction of CYP3A gene transcription. First, PXR is selectively expressed in the liver and intestine, the same tissues in which CYP3A gene expression is induced. Second, PXR binds as a heterodimer with the retinoid X receptor (RXR) to xenobiotic response elements that have been identified in CYP3A gene promoters. Third, PXR is activated by the remarkable array of compounds that are known to induce CYP3A gene transcription. And finally, PXRs from different species are differentially activated by certain compounds such as rifampicin and pregnenolone 16alpha-carbonitrile (PCN) in a manner that correlates with species-specific induction of CYP3A gene expression. We are now employing high throughput PXR activation and binding assays to identify drug candidates that induce CYP3A gene expression so that these compounds can be removed from the drug development process.