- Factors required for mitochondrial function are encoded both by the nuclear and mitochondrial genomes. The order of magnitude higher mutation rate of animal mitochondrial DNA (mtDNA) enforces tight co-evolution of mtDNA and nuclear DNA encoded factors. In this essay we argue that such co evolution exists at the population and inter-specific levels and affect disease susceptibility. We also argue for the existence of three modes of co-evolution in the mitochondrial genetic system, which include the interaction of mtDNA and nuclear DNA encoded proteins, nuclear protein – mtDNA-encoded RNA interaction within the mitochondrial translation machinery and nuclear DNA encoded proteins-mtDNA binging sites interaction in the frame of the mtDNA replication and transcription machineries. These modes of co evolution require co-regulation of the interacting factors encoded by the two genomes. Thus co evolution plays an important role in modulating mitochondrial activity. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.