Although pharmacogenetics has been instrumental in describing interindividual variations in drug metabolism, epigenetic factors offer another blanket of information that could give a more vivid picture and help in developing a more personalized therapy. The dynamic aspect of epigenetics could likewise provide more definite answers to the role of changing environmental factors in drug response: the bridge that connects the environment to the genome. In this review we discuss known epigenetic and microRNA-dependent regulation of the human drug-metabolizing cytochromes P450 to help explain the unknown factors of variable drug response.