The human mitochondrial genome consists of approximately 1500 genes, 37 encoded by the maternally inherited mitochondrial DNA (mtDNA) and the remainder encoded in the nuclear DNA (nDNA). The mtDNA is present in thousands of copies per cell and encodes proteins that are essential components of the mitochondrial energy generation pathway, oxidative phosphorylation (OXPHOS). OXPHOS generates heat to maintain our body temperature and ATP to do work. The mitochondria also produce much of the cellular reactive oxygen species (ROS) and can initiate apoptosis through activation of the mitochondrial permeability transition pore (mtPTP) in response to energy deficiency and oxidative damage. Mitochondrial ROS mutates the mtDNA and mtDNA mutations have been associated with a wide range of age-related diseases including neurodegenerative diseases, cardiomyopathy, diabetes and various cancers. The cellular accumulation of mtDNA mutations may also be the aging clock. Ancient mtDNA variants have also been adaptive and may influence individual health today. Mutations in nDNA-encoded mitochondrial genes can also disrupt OXPHOS, alter mtDNA replication, and affect mitochondrial division. In an effort to treat mitochondrial disease, both metabolic and genetic interventions have been attempted. Metabolic interventions have been directed at increasing energy output, reducing ROS production and stabilizing the mtPTP. Genetic therapies have attempted introduction of nucleic acids into the mitochondrion, nDNA-mitochondrial genes into the nucleus, and mtDNA-encoded genes into the nucleus. These therapeutic approaches might also be used to enhance performance, but we must be careful that catering to short term individual interests might undermine our capacity to adapt and survive.