The myocardium is particularly susceptible to complications from iron loading in thalassemia major. In the first years of life, severe anemia leads to high-output cardiac failure and death if not treated. The necessary supportive blood transfusions create loading of iron that cannot be naturally excreted, and this iron accumulates within tissues, including the heart. Free unbound iron catalyzes the formation of toxic hydroxyl radicals, which damage cells and cause cardiac dysfunction. Significant cardiac siderosis may present by the age of 10 and may lead to acute clinical heart failure, which must be treated urgently. Atrial fibrillation is the most frequently encountered iron-related arrhythmia. Iron chelation is effective at removing iron from the myocardium, at the expense of side effects that hamper compliance to therapy. Monitoring of myocardial iron content is mandatory for clinical management of cardiac risk. T2* cardiac magnetic resonance measures myocardial iron and is the strongest biomarker for prediction of heart failure and arrhythmic events. It has been calibrated to human myocardial tissue iron concentration and is highly reproducible across all magnetic resonance scanner vendors. As survival and patient age increases, endothelial dysfunction and diabetes may become new factors in the cardiovascular health of thalassemia patients. Promising new imaging technology and therapies could ameliorate the long-term prognosis.