The increased capacity to rapidly eliminate drugs can have a profound effect on the efficacious exposure of coadministered drugs, especially in today's medical world of polypharmacy. There are numerous drug-drug interactions (DDIs) related to a loss of therapeutic efficacy and many of these are caused by pregnane X receptor (PXR)-mediated transcriptional activation of drug-metabolizing enzymes or drug transporters. Evaluation of PXR activation and subsequent induction of proteins involved in drug elimination and distribution have become routine in drug discovery and drug development. The assays used to evaluate PXR directly are high throughput and provide useful information on the ability of a drug's potential to precipitate a DDI. In addition, they may serve as useful tools to support structure-activity or structure-liability relationships to eliminate or minimize the potential of new drug candidates to cause induction and, ultimately, a DDI.