Yeast and bovine cytochrome c oxidases (COX) are composed of 12 and 13 different polypeptides, respectively. In both cases, the three subunits constituting the catalytic core are encoded by mitochondrial DNA. The other subunits are all products of nuclear genes that are translated on cytoplasmic ribosomes and imported through different transport routes into mitochondria. Biogenesis of the functional complex depends on the expression of all the structural and more than two dozen COX-specific genes. The latter impinge on all aspects of the biogenesis process. Here we review the current state of information about the functions of the COX-specific gene products and of their relationship to human COX deficiencies.