Drug processing genes (DPGs), namely uptake transporters, phase-I and phase-II enzymes, as well as efflux transporters are responsible for the absorption, distribution, metabolism, and excretion of xenobiotics. The constitutive and/or inducible expression of these DPGs is regulated by a group of nuclear receptors/transcription factors. There is increasing evidence that these DPGs and nuclear receptors are regulated by epigenetic mechanisms, namely DNA methylation, histone modifications, and microRNAs. Herein, we summarize the current state of knowledge of the epigenetic regulation of these DPGs and nuclear receptors, with particular emphasis on roles of epigenetics in regulating tissue-specific expression, changes in gene expression during development, and alterations of gene expression during carcinogenesis.