Altered metabolism and resistance to cell death are typical hallmarks of cancer phenotype. Mitochondria are organelles central to cellular metabolism as well as to cell death induction. Hyperactivation of pro-survival and pro-proliferative pathways such as PI3K/AKT leads to cancer initiation, which affects mitochondria. Growing body of evidence indicates that oncogenes such as HER2, EGFR and RAS, as well as the downstream members of the PI3K/AKT signaling pathway, directly regulate mitochondria by translocating to the organelle. Here we discuss evidence of this scenario and consider mechanisms for direct regulation of mitochondrial function. Being in close proximity to mitochondrial bioenergetics machinery as well as to the regulators/executors of programed cell death, oncogenes in mitochondria may be ideally placed to perform this task. This represents a thus far under-explored area, which may be relevant to better understanding of cancer initiation, progression and treatment.