Bioactive electrophiles generated from the oxidation of endogenous and exogenous compounds are a contributing factor in numerous disease states. Their toxicity is largely attributed to the covalent modification of cellular nucleophiles, including protein and DNA. With regard to protein modification, the side-chains of Cys, His, Lys, and Arg residues are critical targets. This results in the generation of undesired protein post-translational modifications (PTMs) that can trigger dire cellular consequences. Notably, histones are Lys- and Arg-rich proteins, providing a fertile source for adduction by both exogenous and endogenous electrophiles. The regulation of histone PTMs plays a critical role in the regulation of chromatin structure and thus gene expression. This perspective focuses on the role of electrophilic protein adduction within the context of chromatin and its potential consequences on cellular law and order.