The data discussed in this review indicate that the coordinated induction of both the mdr gene family and a subfamily of the cytochrome P-450 supergene family provide a unified response of the organism to prevent lethal accumulation of xenobiotics. Consequently, a distinct physiological role for the mdr multigene family now exists. Furthermore, recent evidence suggests the existence of multiple receptors with overlapping substrate specificity that are involved in the induction of both mdr and P-4501A gene families. The increased expression of mdr gene(s) in the early stages of liver carcinogenesis and presumably in other tissues is associated with the development of xenobiotic resistance that is observed in the preneoplastic cell populations. These observations may have important clinical implications and may provide an explanation for resistance to chemotherapy of tumors in organs such as liver and colon that are frequently exposed to both environmental and dietary xenobiotics.