Retinoid X receptors (RXRs) form heterodimers with pregnane X receptor (PXR) and constitutive androstane receptor (CAR), two prototypical xenobiotic receptors, and mediate metabolism of xenobiotics (foreign compounds) and endobiotics (endogenous compounds). Establishment of gene knockout and transgenic mouse models of RXRs, PXR, and CAR greatly enhanced the study of the biology of nuclear receptors, leading to considerable research progress in understanding the molecular mechanism underlying the nuclear receptor-mediated pathways in xenobiotic and endobiotic metabolism. These animal models are widely used in screening nuclear receptor ligands, identifying nuclear receptor target genes, and defining physiological and pharmacological pathways mediated by these xenobiotic nuclear receptors. In addition, "humanized" PXR and CAR mouse models, which avoid species specificity, provide valuable tools for investigating human xenobiotic response. Moreover, generations of multiple gene knockout mouse models further allow us to identify unique and redundant pathways mediated by each xenosensor. In this article, we review the progress made by using animal models of RXRs, PXR, and CAR in understanding the biological functions of these nuclear receptors in physiology, pharmacology, and pathology.