The epigenome can undergo changes in response to various environmental exposures, such as therapeutic drugs, chemical toxicants, nanoparticle pollution, and electromagnetic radiation. High-throughput technologies allow accurate genome sequencing and high-resolution mapping of epigenetic marks, such as DNA and chromatin modifications. Some epigenetic changes occur concomitantly with transcriptomic and physiological changes, while others appear to be unrelated to other molecular changes at a given time point. An important challenge in the field of toxicology is to integrate these two types of changes with classical toxicology methods, taking into consideration the possible chronological gap between molecular changes and physiological phenotypes. To optimally leverage epigenetic information, toxicologists must overcome fundamental challenges, including technical and computational limitations. Here we review the current knowledge on epigenetic alterations related to environmental exposures, with emphasis on tobacco risk assessment. We also discuss available technologies and their applications in toxicological studies.