The defense mechanisms responsible for protecting the body from endogenous toxins are also involved in the metabolism of drugs and are composed of phase I and phase II drug metabolizing enzymes, as well as drug transporters. Numerous drugs and chemicals have been shown to modulate the expression of the genes involved in these three drug-detoxifying processes. Induction of these genes contributes to both auto-induction of drug clearance and to drug-drug interactions in combination therapies. The orphan nuclear receptors PXR (pregnane X receptor) and CAR (Constitutive androstane receptor) are xenosensors that mediate drug-induced changes by increasing transcription of genes that are involved in drug clearance and disposition. Co-administration of drugs, one of which is a nuclear receptor agonist or antagonist, can either lead to altered clearance of the second drug and severe toxicity, or a loss of therapeutic efficacy or an imbalance in physiological substrate concentrations, providing a novel molecular mechanism for drug-drug interactions. Thus, genetic variability in these nuclear receptors will contribute to human variation in the magnitude of clinically significant drug-drug interactions. This review describes common PXR and CAR genetic variants that have been identified to date in the human population and the functional consequence of these variant alleles. In addition, alternatively spliced variants of PXR and CAR that may also contribute to individual variability as well as tissue specific expression of these receptors are also described. Identification of PXR and CAR genetic variants and alternatively spliced mRNAs may ultimately allow predictions of interindividual differences in target gene induction and drug-drug interactions.