This presentation will provide an overview of (1) in vitro methods currently used and recommended by the FDA to assess the potential of drug candidates to perpetrate drug-drug interactions by inducing human drug-metabolizing enzymes and drug transporters with an emphasis on studies of cytochrome P450 (CYP) enzyme induction in primary cultures of human hepatocytes, and (2) IVIVC methods to extrapolate in vitro findings to the in vivo situation in order to assess the potential for clinically significant induction. For the most part, enzyme induction is a receptor-mediated process that is a clinical concern for victim drugs that have a narrow therapeutic index and that are used to treat life-threatening illnesses (such as anti-HIV and anti-organ-rejection drugs) or drugs with a quantal rather than a graded dose-response relationship (such or oral contraceptive steroids, which either do or do not block ovulation). Enzyme induction is also emerging as an important crossroad between xenobiotics and endobiotics (endogenous chemicals) because activation of xenosensors (i.e., the receptors that mediated enzyme induction, such as AhR, CAR and PXR) can (1) induce the metabolism of endobiotics such the active metabolite of vitamin D (which can result in osteomalacia), (2) alter the function of numerous other receptors and vice versa, which, in the case of NF-κB, accounts in part for the ability of inflammatory processes to suppress the expression and induction of various drug-metabolizing enzymes, and (3) mediate the homeostatic response to high levels of endobiotics such as bilirubin (which activates CAR) and bile acids (which activate PXR in addition to FXR). This presentation will give an overview of the cross-talk among xenosensors and between xenosensors and other nuclear receptors, and will highlight some of the emerging roles that xenosensors have been found to play in endobiotic metabolism.