Anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) are among the most potent chemotherapeutic agents and have truly revolutionized the management of childhood cancer. They form the backbone of chemotherapy regimens used to treat childhood acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin lymphoma, Ewing sarcoma, osteosarcoma, and neuroblastoma. More than 50% of children with cancer are treated with anthracyclines. The clinical utility of anthracyclines is compromised by dose-dependent cardiotoxicity, manifesting initially as asymptomatic cardiac dysfunction and evolving irreversibly to congestive heart failure. Childhood cancer survivors are at a five- to 15-fold increased risk for congestive heart failure compared with the general population. Once diagnosed with congestive heart failure, the 5-year survival rate is less than 50%. Prediction models have been developed for childhood cancer survivors (i.e., after exposure to anthracyclines) to identify those at increased risk for cardiotoxicity. Studies are currently under way to test risk-reducing strategies. There remains a critical need to identify patients with childhood cancer at diagnosis (i.e., prior to anthracycline exposure) such that noncardiotoxic therapies can be contemplated.