PXR, CAR and PPAR, widely distributed in the body, are important members of the nuclear receptors (NRs) family.  The activities and gene expressions of drug-metabolizing enzymes (DMEs) and transporters can be regulated by the activation of NRs, which effect the drug disposition.  Multidrug resistance (MDR) is the leading cause of failure in cancer therapy.  NRs, including PXR, CAR and PPAR, were shown to regulate the expressions of DMEs and transporters involved in the drug metabolism and clearance, suggesting that the modulation of NRs can be considered as a new target to overcome MDR.  This review described the research progress of NR family members PXR, CAR, PPAR and their transcriptional activation mechanism, the regulation of DMEs and transporters by NRs, which may provide a valuable reference for clinical medication and overcome of MDR.