Children diagnosed with cancer are commonly treated with anthracyclines, which have increased the number of survivors to more than 325,000 in the United States. However, anthracyclines are limited by their cardiotoxicity, which increases the risk of treatment-related complications. Survivors are more likely than their healthy siblings to experience heart failure, coronary artery disease, and stroke within the first 30 years after diagnosis. The mechanisms of anthracycline cardiotoxicity are not well understood. Cardiotoxicity can develop any time, from the start of chemotherapy to decades after its completion, and can manifest sub-clinically (e.g., echocardiographic abnormalities) or clinically (e.g., heart failure). However, not all survivors are affected equally, despite receiving similar doses of anthracyclines. Factors such as age at diagnosis, female sex, and cumulative anthracycline dose are risk factors for cardiotoxicity. Possible genetic risk factors that may explain the variability among survivors need to be explored. Identifying the highest-risk patients may help inform the frequency of monitoring during and after treatment and identify those who would benefit most from other treatment and prevention options, such as limiting the cumulative dose of anthracyclines, replacing them with liposomal anthracyclines, and using dexrazoxane as a cardioprotectant. The ultimate goal is to maximize the oncologic efficacy of anthracyclines and to minimize their late cardiotoxic effects in the vulnerable and less-studied population of childhood cancer survivors.