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Cocaine is extensively used as a psychostimulant among subjects at different ages worldwide. Cocaine causes neuronal dysfunction and, consequently, negatively affects human behavior and decreases life quality severely. Cocaine acts through diverse mechanisms, including mitochondrial impairment and activation of cell signaling pathways associated to stress response. There is some controversy regarding the effect of cocaine in inducing cell death through apoptosis in different experimental models. The aim of the present work is to discuss data associated to the mitochondrial consequences of cocaine exposure of mammalian cells in several experimental models from in vitro to in vivo, including postmortem human tissue analyses. Furthermore, future directions are proposed in order to serve as a suggestive guide in relation to the next steps towards the complete elucidation of the mechanisms of toxicity elicited by cocaine upon mitochondria of neuronal cells.Cocaine induces mitochondrial dysfunction in brain cells.Cocaine elicits mitochondria-associated cell death in brain cells.Further research is necessary to examine how cocaine interacts with mitochondria.