Therapeutic ionizing radiation, such as that used in the treatment of Hodgkin's lymphoma, can cause cardiac valvular damage that may take several years to manifest as radiation-associated valvular heart disease. Treatment can be complicated by comorbid radiation injury to other cardiac and mediastinal structures that lead to traditional surgical valve replacement or repair becoming high-risk. A representative case is presented that demonstrates the complexity of radiation-associated valvular heart disease and its successful treatment with percutaneous transcatheter valve replacement. The prevalence and pathophysiologic mechanism of radiation-associated valvular injury are reviewed. Anthracycline adjuvant therapy appears to increase the risk of valvular fibrosis. Left-sided heart valves are more commonly affected than right-sided heart valves. A particular pattern of calcification has been noted in some patients, and experimental data suggest that radiation induction of an osteogenic phenotype may be responsible. A renewed appreciation of the cardiac valvular effects of therapeutic ionizing radiation for mediastinal malignancies is important, and the treatment of such patients may be assisted by the development of novel, less-invasive approaches.