With the advent of high resolution sequencing technologies there has been increasing interest in the study of genome-wide epigenetic modification patterns that govern the underlying gene expression events of a particular cell or tissue type. There is now mounting evidence that perturbations to the epigenetic landscape occur during a host of cellular processes including normal proliferation/differentiation and aberrant outcomes such as carcinogenesis. Furthermore, epigenetic perturbations have been associated with exposure to a range of drugs and toxicants, including non-genotoxic carcinogens (NGCs). Although a variety of epigenetic modifications induced by NGCs have been studied previously, recent genome-wide integrated epigenomic and transcriptomic studies reveal for the first time the extent and dynamic nature of the epigenetic perturbations resulting from xenobiotic exposure. The interrogation and integration of one such epigenetic mark, the newly discovered 5-hydroxymethylcytosine (5hmC) modification, reveals that drug treatment associated perturbations of the epigenome can result in unique epigenetic signatures. This review focuses on how recent advances in the field of epigenetics can enhance our mechanistic understanding of xenobiotic exposure and provide novel safety biomarkers. Crown Copyright © 2013.