Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin (DOX) is one of the most highly prescribed anthracyclines in the USA, due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of DOX cardiotoxicity, contributing to the development of cardiomyopathy. The present review provides the basis for the involvement of mitochondrial toxicity in the different functional hallmarks of anthracycline toxicity. Our objective is to understand the molecular determinants of a progressive deterioration of functional integrity of mitochondria that establishes an historic record of past drug treatments (“mitochondrial memory”) and renders the cancer patient susceptible to subsequent regimens of drug therapy. We focus on the involvement of DOX-induced mitochondrial oxidative stress, disruption of mitochondrial oxidative phosphorylation and in the permeability transition, contributing to altered metabolic and redox circuits in cardiac cells, ultimately culminating in disturbances of autophagy/mitophagy fluxes, and increased apoptosis. We also suggest some possible pharmacological and non-pharmacological interventions that can reduce mitochondrial damage. Understanding the key role of mitochondria in DOX-induced cardiomyopathy is essential to reduce the barriers that so dramatically limit the clinical success of this essential anticancer chemotherapy.