Although conventional doxorubicin is associated with favorable clinical outcomes in patients with a variety of tumor types, it long has been associated with the risk of development of cardiotoxicity. Therefore, researchers have focused their efforts on the development of new formulations to improve efficacy while minimizing associated toxicities. The most successful strategy reported to date has been liposomal encapsulation, which alters the pharmacokinetics of the drug, with the goal of maintaining efficacy and improving the therapeutic index. The cardiac profiles of three liposomal anthracyclines, liposomal daunorubicin, nonpegylated liposomal doxorubicin, and pegylated liposomal doxorubicin, were reviewed. More studies will be needed to determine the cardiac safety of liposomal daunorubicin. Although nonpegylated liposomal doxorubicin demonstrated more favorable cardiac safety compared with conventional doxorubicin, its cardiac safety appeared to be mitigated when high bolus doses were administered. Of the liposomal formulations, the strongest evidence of cardiac safety was observed with pegylated liposomal doxorubicin. Compared with conventional doxorubicin, pegylated liposomal doxorubicin was associated with a significantly lower risk of development of cardiac events (P < 0.001). Moreover, the risk of cardiotoxicity was not increased in patients who were treated with pegylated liposomal doxorubicin at cumulative doses > 450 mg/m2 or in patients at increased risk for cardiotoxicity, such as those with prior adjuvant doxorubicin use. Liposomal doxorubicin formulations provided a favorable advantage over conventional doxorubicin in terms of cardiac safety. Recent evidence also suggests that the improved cardiac safety of liposomal doxorubicin formulations is reflected by their successful use in combination with trastuzumab and other chemotherapy agents. Cancer 2004. © 2004 American Cancer Society.