Evolution in allopatric populations can lead to incompatibilities that result in reduced hybrid fitness and ultimately reproductive isolation upon secondary contact. The Dobzhansky–Muller (DM) model nicely accounts for the evolution of such incompatibilities. Although DM incompatibilities were originally conceived as resulting of interactions between nuclear genes, recent studies have documented cases where incompatibilities have arisen between nuclear and mitochondrial genomes (mtDNA). Although mtDNA comprises only a tiny component (typically ≪0.01%) of an organism's genetic material, several features of mtDNA may lead to a disproportionate contribution to the evolution of hybrid incompatibilities: (i) essentially all functions of mtDNA require interaction with nuclear gene products. All mtDNA-encoded proteins are components of the oxidative phosphorylation (OXPHOS) system and all mtDNA-encoded RNAs are part of the mitochondrial protein synthetic machinery; both processes require interaction with nuclear-encoded proteins for function. (ii) Transcription and replication of mtDNA also involve mitonuclear interactions as nuclear-encoded proteins must bind to regulatory motifs in the mtDNA to initiate these processes. (iii) Although features of mtDNA vary amongst taxa, metazoan mtDNA is typically characterized by high nucleotide substitution rates, lack of recombination and reduced effective population sizes that collectively lead to increased chance fixation of mildly deleterious mutations. Combined, these features create an evolutionary dynamic where rapid mtDNA evolution favours compensatory nuclear gene evolution, ultimately leading to co-adaptation of mitochondrial and nuclear genomes. When previously isolated lineages hybridize in nature or in the lab, intergenomic co-adaptation is disrupted and hybrid breakdown is observed; the role of intergenomic co-adaptation in hybrid breakdown and speciation will generally be most pronounced when rates of mtDNA evolution are high or when restricted gene flow results in significant population differentiation.