Diet-related mutagenesis plays an etiologic role in chronic diseases, including cardiovascular disease and cancer. Many dietary mutagens are DNA reactive, leading to distinct spectra of base-pair substitution mutations and structural chromosome changes. Examples include aflatoxin B1, ochratoxin A, ptaquiloside, various pyrrolizidine alkaloids, heterocyclic amines including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and polycyclic aromatic hydrocarbons such as benzo[a]pyrene. However, endogenously or exogenously formed reactive species, inhibitors of topoisomerase II enzymes (e.g., flavonoids), of DNA repair (e.g., caffeine), or of the mitotic spindle (possibly acrylamide), also cause mutations, including structural chromosome changes and copy number variants. Genomic instability also results from inadequate nutrient intake (e.g., folate and selenium). Antimutagens include vitamin C, carotenoids, chlorophyllin, dietary fibers, and plant polyphenols acting through various mechanisms. Polymorphisms in genes for nutrient uptake, metabolism, and excretion will affect dietary intake in determining individual risk of disease development. Human studies utilizing nutrigenomic/nutrigenetic technologies will be essential to quantifying and overcoming diet-related mutagenesis.