Environmental and occupational exposures to both natural and anthropogenic substances are known to play a causative role in carcinogenesis. While it is well accepted that carcinogenesis occurs by both genotoxic and non-genotoxic mechanisms, genotoxicity has been more thoroughly studied. Accumulating evidence suggests that epigenetic alterations also play an important role in chemically-induced carcinogenesis, and that these changes to the epigenome may be as important as genotoxicity. To gain a better understanding of the epigenetic alterations that occur as a consequence of exposure to a genotoxic chemical, we evaluated genetic and epigenetic alterations in two mouse models of genotoxicity. First, to determine the relative contribution of these molecular changes in liver tumorigenesis, we evaluated epigenetic modifications and the mutational profile of genes commonly altered in liver tumors in mice treated with a combination of a genotoxic and a pro-fibrogenic agent. Marked epigenetic changes in liver tumors and surrounding fibrotic liver tissue were associated with tumor incidence, while mutations in known cancer-related genes were not observed. Second, to better characterize the diverse molecular mechanisms of 1,3-butadiene (BD)-induced tumorigenicity, we evaluated DNA adducts and epigenetic alterations caused by exposure to BD in a set of two genetically divergent mouse strains (C57BL/6J and CAST/EiJ) and across both target (lung and liver) and non-target (kidney) tissues of BD-induced tumorigenesis. Although BD-DNA adducts were observed in all three tissues and both strains of BD-exposed mice, epigenetic alterations were clearly tissue- and strain-specific. These results suggest that epigenetic alterations represent a disease-relevant class of specific, and potentially mechanistically important, molecular features that are involved in chemically-induced carcinogenesis. Our findings emphasize the necessity of inclusion of epigenetic marks in assessment of potential and known cancer hazards.