This review focuses on molecular mechanisms that underlie the communication between the nuclear and mitochondrial genomes in eukaryotic cells. These genomes interact in at least two ways. First, they contribute essential subunit polypeptides to important mitochondrial proteins; second, they collaborate in the synthesis and assembly of these proteins. The first type of interaction is important for the regulation of oxidative energy production. Isoforms of the nuclear-coded subunits of cytochrome c oxidase affect the catalytic functions of its mitochondrially coded subunits. These isoforms are differentially regulated by environmental and developmental signals and probably allow tissues to adjust their energy production to different energy demands. The second type of interaction requires the bidirectional flow of information between the nucleus and the mitochondrion. Communication from the nucleus to the mitochondrion makes use of proteins that are translated in the cytosol and imported by the mitochondrion. Communication from the mitochondrion to the nucleus involves metabolic signals and one or more signal transduction pathways that function across the inner mitochondrial membrane. An understanding of both types of interaction is important for an understanding of OXPHOS diseases and aging.