The regulation of the oxidative phosphorylation system (OXPHOS) biogenesis in eukaryotic cells is unique since it involves the expression of two genomes, the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA). The considerable effort done in collecting information on the factors that influence the expression of the genes encoded in mtDNA and nDNA has revealed that a multiplicity of regulatory options are available in mammalian cells to perform this task. Thus, at least three archetypal situations can be distinguished: mitochondrial proliferation, mitochondrial differentiation, and mitochondrial local tuning (MLT). Each of them seems to be predominantly under the control of specific strategies of regulation, although the description of the detailed molecular mechanisms involved is still in its beginnings. In the present review, we focus on the evidence supporting the existence of mechanisms for autonomous regulation of mtDNA transcription and its role in the integrated regulation of the OXPHOS system biogenesis.