The clinical use of doxorubicin and other quinone-hydroquinone anticancer anthracyclines is limitedby a dose-related cardiotoxicity. Here, we review the correlation of cardiotoxicity of doxorubicinwith its peak plasma concentration and diffusion in the heart, followed by reductive bioactivation or oxidativeinactivation. One-electron quinone reduction and two-electron side chain carbonyl reduction are accompaniedby iron and free radical reactions that are responsible for many aspects of anthracycline cardiotoxicity.In contrast, one-electron hydroquinone oxidation serves as a salvage pathway for degrading and detoxifyinganthracyclines. Mechanism-based cardioprotective strategies therefore involve replacing bolus administrationwith slow infusions (to reduce the drug's plasma peak), encapsulating anthracyclines in liposomes (to reducethe drug's cardiac diffusion), and administering antioxidants or iron chelators. Preclinical modellingand clinical studies suggest that eliminating the side chain carbonyl group reduction warranted a satisfactorydegree of cardioprotection. Approved or investigational anthracyclines that lacked the carbonyl group orshowed an inherent resistance to carbonyl reduction might prove safer than doxorubicin, particularly whenadministered with new generation drugs that otherwise caused a toxic synergism with doxorubicin.