Conventional anthracyclines are active against many tumor types, but cardiotoxicity related to the cumulative dose may limit their use; this is particularly problematic for patients with risk factors for increased toxicity, for those who have received any anthracycline in the past, or for those who are to receive other cardiotoxic agents. Preclinical studies determined that encapsulating conventional anthracyclines in liposomes reduced the incidence and severity of cumulative dose-related cardiomyopathy while preserving antitumor activity. In controlled clinical trials, the risk of cardiotoxicity was significantly lower when nonpegylated liposomal doxorubicin (Myocet [NPLD]) was substituted for conventional doxorubicin, but the risk was not significantly different when NPLD was used in place of conventional epirubicin. Direct comparisons to conventional doxorubicin therapy showed comparable efficacy but significantly lower risk of cardiotoxicity with pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) therapy. Retrospective and prospective trials have not identified a maximum "cardiac safe" dose of PLD, despite use of cumulative doses exceeding 2,000 mg/m2 in some patients. Liposomal daunorubicin (DaunoXome [DNX]) may be associated with a lower risk of cardiotoxicity than conventional anthracyclines, but comparative trials are not available. With respect to combination chemotherapy, early results of clinical trials suggest that combining trastuzumab or a taxane with NPLD or PLD instead of a conventional anthracycline significantly reduces cardiotoxicity risk without reducing chemotherapeutic efficacy. Further results are eagerly awaited from ongoing controlled trials of cardiac safety with long-term liposomal anthracycline therapy, either alone or in combination with other potentially cardiotoxic agents.