Mediastinal radiation therapy accelerates the atherosclerosis process, resulting in early onset coronary artery disease. Valvular disease due to radiation therapy typically affects the left-sided valves, with aortic regurgitation being the most common. Rarely, it may lead to aortic stenosis requiring surgical interventions. Pericardial involvement includes acute and chronic pericardial disease and pericardial effusion. New studies are investigating the prevalence and pathogenesis of autonomic dysfunction in cancer survivors who have undergone mediastinal and neck radiation. Radiation therapy itself causes vascular endothelial dysfunction, resulting in clinical cardiovascular events, manifesting many years after completion of therapy. There remains little guidance regarding screening and therapies to prevent cardiovascular events in this population.