Cellular resistance to anthracyclines is often associated with an unfavorable clinical outcome in a variety of cancers, including leukemia. Several mechanisms of anthracycline resistance may be involved such as an impaired transport of drugs across the plasma membrane, an increased drug efflux, an increased intracellular detoxification of drugs, a reduced availability of intracellular drug targets, or a reduced ability of cells to induce apoptosis. Here, we review the studies published about mechanisms which may explain resistance to anthracyclines in leukemic cells of pediatric patients.