Anthracyclines are powerful anticancer drugs whose use is limited by the development of chronic cardiotoxicity. The bisdioxopiperazine compound ICRF-187 (ADR-529) specifically abrogates this toxicity both in preclinical animal models and in humans. It does this without effecting either the acute toxicities or the anticancer activity. Therefore, with a specific antagonist, the mechanism of activity of the anthracyclines can be explored. This review discusses recent clinical trials and animal models addressing this issue and concludes by hypothesizing a mechanism of action.