Anthracyclines are among the most active antineoplastic drugs developed to date, used both in the treatment of solid cancers, such as breast and ovarian cancer and sarcomas, and of hematologic cancers. However, their clinical use is limited by cardiotoxicity, which is observed at a range of 0.4-41%. The risk of this side effect can be minimized by using cardioprotective agents, planning dosing schedules to lower the anthracycline peak plasma concentration, identifying and monitoring high-risk patients, keeping in mind that early anthracycline-induced histologic changes may be identified successfully by cardiac biopsy. Nonetheless, the challenge to increase the tumor response to chemotherapy while keeping low the cardiac risk may be now met by the use of a recently introduced polyethylene glycol-coated (pegylated) liposomal doxorubicin (PLD). Here, we review the pharmacologic properties of PLD as well as the results of phases I, II and III trials demonstrating activity and low cardiac toxicity associated with the use of this novel drug.