Research of the role of oxidative DNA damage is well established in experimental carcinogenesis. A large number of human studies on biomarkers of oxidative DNA damage, in particular related to guanine oxidation, have been published. The level of oxidative DNA damage and repair activity can be quite different between tumor and normal tissues; case-control studies have shown increased levels of oxidative DNA damage and decreased repair capacity in leukocytes from cases. Similarly, the urinary biomarkers of oxidative DNA damage may be elevated in patients with cancer. However, such studies are likely to be associated with reverse causality. Case-control studies of genetic polymorphisms in DNA repair enzymes suggest that the common variant Ser326Cys in OGG1 may be a risk factor for lung cancer, whereas a rare variant in OGG1 and germ line mutations in the corresponding mismatch repair gene MYH are risk factors for hereditary colon cancer. Cohort studies are required to provide evidence that a high level of oxidative DNA damage implies a high risk of cancer. However, this represents a real challenge considering the large number of subjects and long followup time required with likely spurious oxidation of DNA during collection, assay and/or storage of samples.