As well-known, IR exposure can be considered for humans as a double-edged sword to either hurt or save. On one hand it can induce significant levels of complex and usually unrepairable DNA damage that can lead to enhanced mutation levels, GI and cancer, but on the other hand it can be used as the ultimate weapon against tumors . Treatment options for patients with various kinds of malignancies have expanded with discoveries of druggable targets as well as technological advances. Surgical resection, chemotherapy and RT are the three major available modalities for the treatment of most cancers and are utilized either in combination or separately, as deemed appropriate. In case of chemotherapy and RT, the main aim is to spare normal cells while inducing sufficient, non-repairable DNA damage in tumor cells. Consequently, cancer cells may exit the cell cycle permanently, a phenomenon referred to as senescence, or triggered apoptosis. The mechanism of action of chemotherapeutic agents and the dose and type of RT determines the spectrum of DNA damage induced by treatment. As discussed earlier, complex DNA lesions are the most challenging type of damage for a cell to repair. This section focuses on whether there is evidence linking efficacy of chemotherapeutic drugs or RT to the type of DNA damage they incur. Additionally, a discussion is made on evidence from literature that highlights the drawback of using these agents for therapy, since normal cells affected by these insults to their DNA can also lead to a second primary cancer development.