The clinical use of anticancer anthracyclines is limited by the development of a distinctive and life-threatening form of cardiomyopathy upon chronic treatment. Commonly accepted mechanistic hypotheses have assigned a pivotal role to iron, which would act as a catalyst for free radical reactions and oxidative stress. Although perhaps involved in acute aspects of anthracycline cardiotoxicity, the role of free radical-based mechanisms in long-term effects has been challenged on both experimental and clinical grounds, and alternative hypotheses independent of iron and free radicals have flourished. More recently, studies of the role of C-13 hydroxy metabolites of anthracyclines have provided new perspectives on the role of iron in the cardiotoxicity of these drugs, showing that such metabolites can impair intracellular iron handling and homeostasis. The present review applies a multisided approach to the critical evaluation of various hypotheses proposed over the last decade for the role of iron in anthracycline-induced cardiotoxicity. The main goal of the authors is to build a unifying pattern that would both account for hitherto unexplained experimental observations and help design novel and more rational strategies toward a much-needed improvement in the therapeutic index of anthracyclines.