During the last few decades, a considerable amount of work has been done to better assess the effects of ionizing radiation on living organisms. In particular a lot of attention has been focused on the consequences of modifications of the DNA macromolecule, the support of the genetic information. Detailed information is now available on the formation of radiation-induced DNA lesions at the physical, chemical and biological levels. Emphasis will be placed in this review article on the differences and similarities, in term of DNA lesions formation and outcome, between endogenous oxidative stress and ionizing radiation, both stresses that could produce oxidative DNA lesions through similar mechanistic pathways involving mostly reactive oxygen species. If the chemical nature of the generated lesions is similar, the differences in term of biological consequences could be attributed to their spatial distribution in genomic DNA, since ionizing radiations produce lesions in cluster. These clusters of lesions represent a challenge for the DNA repair machinery. In contrast, endogenous oxidative stress generates scattered lesions that could be repaired with a much higher efficacy and fidelity. Possible implication of the use of DNA damage and repair for human health purposes and radiological protection will be discussed.