The Pregnane X Receptor (PXR) is pivotal for the body's response to toxic xenobiotics and endogenous metabolites. By acting as a ligand-activated transcription factor, PXR regulates all stages of xenobiotic metabolism and transport and is responsible for important inductive drug interactions. Screening assays to assess the PXR activation potential of new and existing drugs are becoming integral components of drug discovery programs. PXR is also involved in lipid homeostasis providing opportunities for treatments based on PXR agonists for diseases involving aberrant cholesterol and bile acid levels. The expression of PXR in many other tissues besides liver and intestine suggest PXR may have additional protective functions in the body, which contribute to disease outcomes in diverse clinical situations with potential for novel therapeutic approaches.