Etheno (epsilon) modified DNA bases (epsilond A, epsilond C, epsilond G) are generated from the carcinogens vinyl chloride and urethane, but also by reactions of DNA with products derived from lipid peroxidation (LPO) and oxidative stress via endogenous pathways. Recently developed ultrasensitive methods allowed the detection of these epsilon-adducts in vivo and their role to be studied in experimental and human carcinogenesis. Highly variable background levels of epsilon-adducts were detected in DNA from different organs of unexposed humans and rodents. Several known cancer risk factors increased the level of these DNA lesions in target organs: elevated epsilon-adducts were found in hepatic DNA from patients with metal storage diseases, after overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) in a mouse model, and in colonic polyps of familial adenomatous polyposis patients. A high omega-6-polyunsaturated fatty acid diet increased epsilon-DNA adducts in white blood cells of female subjects. In conclusion, epsilon-adducts were found to be elevated in cancer-prone tissues, suggesting that these promutagenic lesions could drive cells to malignancy. Therefore, exocyclic DNA adducts offer new tools in cancer aetiological research and in verifying the efficacy of chemopreventive agents.