Increased production of reactive oxygen species during oxidative stress can initiate the formation of lipid hydroperoxides, which undergo homolytic decomposition to the α, β-unsaturated aldehydic bifunctional electrophiles, 4-oxo-2(E)- nonenal (ONE), 4-hydroxy-2(E)-nonenal (HNE), 4-hydroperoxy-2(E)-nonenal (HPNE), and malondialdehyde (MDA). Excessive lipid hydroperoxides can also be derived from the up-regulation of lipoxygenases (LOXs) and cyclooxygenases (COXs). Intracellular generation of the bifunctional electrophiles can then result in the formation of glutathione (GSH), protein, and DNA adducts. The analysis of lipid hydroperoxide-derived DNA adducts, such as ONE-derived heptanone-etheno DNA (HεDNA) adducts, can facilitate molecular epidemiology studies by providing insight into the amount of a genotoxin that has reached the DNA of the tissue under study. In addition, HεDNA adducts that are repaired and excreted in the urine can be used as specific biomarkers of lipid peroxidation-mediated DNA damage.