Radiation-induced heart disease (RIHD) is a potentially severe side effect of radiotherapy of thoracic and chest wall tumors if all or part of the heart was included in the radiation field. RIHD presents clinically several years after irradiation and manifestations include accelerated atherosclerosis, pericardial and myocardial fibrosis, conduction abnormalities, and injury to cardiac valves. There is no method to prevent or reverse these injuries when the heart is exposed to ionizing radiation. This paper presents an overview of recent studies that address the role of microvascular injury, endothelial dysfunction, mast cells, and the renin angiotensin system in animal models of cardiac radiation injury. These insights into the basic mechanisms of RIHD may lead to the identification of targets for intervention in this late radiotherapy side effect.