Two genomes regulate the energy metabolism of eukaryotic cells: the nuclear genome, which codes for most cellular proteins, and the mitochondrial genome, which, together with the nuclear genome, coregulates cellular bioenergetics. Therefore, mitochondrial genome variations can affect, directly or indirectly, all energy-dependent cellular processes and shape the metabolic state of the organism. This review provides a current and up-to-date overview on how codependent these two genomes are, how they appear to have coevolved, and how variations within the mitochondrial genome might be associated with the manifestation of metabolic diseases. This review summarizes and structures results obtained from epidemiological studies that identified links between mitochondrial haplogroups and individual risks for developing obesity and diabetes. This is complemented by findings on the compatibility of mitochondrial and nuclear genomes and cellular bioenergetic fitness, which have been acquired from well-controlled studies in conplastic animal models. These elucidate, more mechanistically, how single-nucleotide variants can influence cellular metabolism and physiology. Overall, it seems that certain mitochondrial genome variations negatively affect mitochondrial-nuclear compatibility and are statistically linked with the onset of metabolic diseases, whereas, for others, greater uncertainty exists, and additional research into this exciting field is required.