Ionizing radiation (IR), as well as a wide variety of chemicals and reactive oxygen species, can cause insults in DNA integrity. However, IR is distinct from other agents in that produces clustered DNA damage, particularly double-strand DNA breaks (DSBs). The discovery of radiosensitive human diseases has revealed that the molecular mechanisms underlying the biological effects of IR impact cellular responses to and repair of DSBs. One class of diseases, including ataxia-telangiectasia, displays a defect in checkpoint response to DSBs. Another class of diseases exhibits severe combined immunodeficiency and defects in DSB repair. Importantly, radiosensitive human diseases are also associated with increased risks of leukemia/lymphoma. In this review, we summarize the molecular nature of IR-induced DNA damage, and provide an overview of the molecular mechanisms of checkpoint response to and repair of DSBs. Lastly, we discuss the roles of these mechanisms in the development of the immune system and the suppression of lymphoma/leukemia, based on the clinical features and experiments with model mice.