The human cytochrome oxidase complex is a multisubunit assembly in the inner mitochondrial membrane responsible for the terminal event in electron transport in which molecular oxygen is reduced. Various phenotypic forms of cytochrome oxidase deficiency have been recognized, the major varieties involving degeneration of the brain stem and basal ganglia (Leigh syndrome) and lactic acidemia. Others include a fatal infantile form, a benign reversible form, and forms with cardiomyopathy. Early recognition of complementation groups within, for instance, the Leigh syndrome group has recently been followed up with a description of the gene defect for three of the nuclear-encoded forms of cytochrome c oxidase (COX) deficiency. The three genes indicted, SURF1 for Leigh syndrome, COX 10 for leukodystrophy and tubulopathy, and SCO2 for the cardiomyopathic form, all have a role in the assembly of the mature cytochrome oxidase complex. The description of these gene defects and the role these genes play are discussed in terms of what can be learned about COX assembly and about the etiology of the different phenotypic forms of the disease.