Doxorubicin (Adriamycin®) is a potent and broad-spectrum antineoplastic agent prescribed for the treatment of a variety of cancers, including both solid tumours and leukaemias. Unfortunately, despite its broad effectiveness, long-term therapy with doxorubicin is associated with a high incidence of a cumulative and irreversible dilated cardiomyopathy. Numerous mechanisms have been proposed to account for this toxicity. Although there is general consensus that doxorubicin undergoes redox cycling to generate free radicals that are responsible for mediating the various cytopathologies associated with drug exposure, the source and subcellular targets continue to be debated. This short review provides a synopsis of the evidence implicating cardiac mitochondria as key intracellular targets, both as sites of generation of highly reactive free radical intermediates as well as targets for the interference with cell calcium regulation and bioenergetic failure that are hallmarks of doxorubicin-induced cardiac failure.