Carcinogenic metals, such as nickel, arsenic, and chromium, are widespread environmental and occupational pollutants. Chronic exposure to these metals has been connected with increased risks of numerous cancers and as well as non-carcinogenic health outcomes, including cardiovascular disease, neurologic deficits, neuro-developmental deficits in childhood, and hypertension. However, currently the specific molecular targets for metal toxicity and carcinogenicity are not fully understood. Here, we propose that the iron- and 2-oxoglutarate-dependent dioxygenase family enzymes, as well as, other histone modifying enzymes are important intracellular targets that mediate the toxicity and carcinogenicity of nickel, and maybe potential targets in chromium and arsenic induced carcinogenesis. Our data demonstrate that all three metals are capable of inducing post-translational histone modifications and affecting the enzymes that modulate them (i.e. the iron- and 2-oxoglutarate-dependent dioxygenase family, including HIF-prolyl hydroxylase PHD2, histone demethylase JHDM2A/JMJD1A, and DNA repair enzymes ABH3 and ABH2, and histone methyltransferases, G9a). Given the effects that these metals can exert on the epigenome, future studies of their involvement in histone modifying enzymes dynamics would deepen our understanding on their respective toxicities and carcinogenicities.