Cancer patients receiving anthracycline-based chemotherapy are at risk to develop life-threatening chronic cardiotoxicity with the pathophysiological mechanism of action not fully understood. Besides the most common hypothesis that anthracycline-induced congestive heart failure (CHF) is mainly caused by generation of reactive oxygen species, recent data point to a critical role of topoisomerase II beta (TOP2B), which is a primary target of anthracycline poisoning, in the pathophysiology of CHF. As the use of the only clinically approved cardioprotectant dexrazoxane has been limited by the FDA in 2011, there is an urgent need for alternative cardioprotective measures. Statins are anti-inflammatory and anti-oxidative drugs that are clinically well established for the prevention of cardiovascular diseases. They exhibit pleiotropic beneficial properties beyond cholesterol-lowering effects that most likely rest on the indirect inhibition of small Ras homologous (Rho) GTPases. The Rho GTPase Rac1 has been shown to be a major factor in the regulation of the pro-oxidative NADPH oxidase as well as in the regulation of type II topoisomerase. Both are discussed to play an important role in the pathophysiology of anthracycline-induced CHF. Therefore, off-label use of statins or novel Rac1 inhibitors might represent a promising pharmacological approach to gain control over chronic cardiotoxicity by interfering with key mechanisms of anthracycline-induced cardiomyocyte cell death.