The cellular consequences of deficiencies of the mitochondrial OXPHOS system include a variety of direct and secondary changes in metabolite homeostasis, such as ROS, Ca(2+), ADP/ATP, and NAD/NADH. The adaptive responses to these changes include the transcriptional responses of nuclear and mitochondrial genes that are mediated by these metabolites, control of the mitochondria permeability transition pore, and a great variety of secondary signalling elements. Among the transcriptional responses reported over more than a decade using material harboring mtDNA mutations, deletions, or depletions, nuclear and mitochondrial DNA OXPHOS genes have mostly been up-regulated. However, it is evident from the limited data in a variety of disease models that expression responses are highly diverse and inconsistent. In this article, the mechanisms and controlling elements of these transcriptional responses are reviewed. In addition, the elements that need to be evaluated, in order to gain an improved perspective of the manner in which OXPHOS genes respond and impact on mitochondrial disease expression, are highlighted.