The Life Span Study of Japanese atomic bomb survivors demonstrates that radiation exposure significantly increased the risk of developing ischemic heart disease, in particular myocardial infarction. Similarly, epidemiologic investigations in very large populations of patients who had received postoperative radiotherapy for breast cancer or for peptic ulcer demonstrate that radiation exposure of the heart with an average equivalent single dose of approximately 2 Gy significantly increased the risk of developing ischemic heart disease more than 10 years after irradiation. These epidemiologic findings are compatible with radiobiologic data on the pathogenesis of radiation-induced heart disease in experimental animals. The critical target structure appears to be the endothelial lining of blood vessels, in particular arteries, leading to early functional alterations such as pro-inflammatory responses and other changes, which are slowly progressive. Research should concentrate on the interaction of these radiation-induced endothelial changes with the early stages of age-related atherosclerosis to develop criteria for optimizing treatment plans in radiotherapy and also potential interventional strategies.