Energy metabolism and mitochondrial function hold a core position in cellular homeostasis. Oxidative metabolism is regulated at multiple levels, ranging from gene transcription to allosteric modulation. To accomplish the fine tuning of these multiple regulatory circuits, the nuclear and mitochondrial compartments are tightly and reciprocally controlled. The fact that nuclear encoded factors, PPARγ coactivator 1α and mitochondrial transcription factor A, play pivotal roles in the regulation of oxidative metabolism and mitochondrial biogenesis is paradigmatic of this crosstalk. Here we provide an updated survey of the genetic and epigenetic mechanisms involved in the control of energy metabolism and mitochondrial function. Chromatin dynamics highly depends on post-translational modifications occurring at specific amino acids in histone proteins and other factors associated to nuclear DNA. In addition to the well characterized enzymes responsible for histone methylation/demethylation and acetylation/deacetylation, other factors have gone on the “metabolic stage”. This is the case of the new class of α-ketoglutarate-regulated demethylases (Jumonji C domain containing demethylases) and of the NAD+-dependent deacetylases, also known as sirtuins. Moreover, unexpected features of the machineries involved in mitochondrial DNA (mtDNA) replication and transcription, mitochondrial RNA processing and maturation have recently emerged. Mutations or defects of any component of these machineries profoundly affect mitochondrial activity and oxidative metabolism. Finally, recent evidences support the importance of mtDNA packaging in replication and transcription. These observations, along with the discovery that non-classical CpG islands present in mtDNA undergo methylation, indicate that epigenetics also plays a role in the regulation of the mitochondrial genome function.