Until even only a few years ago, the idea that effective therapies for human mitochondrial disorders resulting from the dysfunction of the respiratory chain/oxidative phosphorylation system (OxPhos) could be developed was unimaginable. The obstacles to treating diseases caused by mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), and which had the potential to affect nearly every organ system, seemed overwhelming. However, although clinically applicable therapies remain largely in the future, the landscape has changed dramatically and we can now envision the possibility of treating some of these disorders. Among these are techniques to upregulate mitochondrial biogenesis, enhance organellar fusion and fission, "shift heteroplasmy" and eliminate the burden of mutant mtDNAs via cytoplasmic transfer.