Faulty oxidative phosphorylation (OXPHOS) is observed in a number of mitochondrial disorders, and may be associated with single or multiple defects of the five complexes of the respiratory chain. From the genetic standpoint, the respiratory chain is unique as it is formed by means of the complementation of two separate genetic systems: the nuclear genome and the mitochondrial genome. The nuclear genome encodes most of the protein subunits of the respiratory complexes and most of the mtDNA replication and expression systems, whereas the mitochondrial genome encodes only 13 OXPHOS subunits and some RNA components of the mitochondrial translation apparatus. Accordingly, mitochondrial disorders due to defects in oxidative phosphorylation include both Mendelian-inherited and cytoplasmic-inherited diseases. Although our knowledge of these diseases has grown at an impressive rate in the past few years, it is worth noting that, as a result of complementation in the respiratory chain of nuclear-encoded and mitochondrially-encoded polypeptides, it is often difficult to establish a precise relationship between genomic mutations and biochemical phenotypes, or to distinguish pathogenic mutations from polymorphic variants in gene sequences. This review deals with human diseases due to mutations of the structural components of the respiratory chain, particularly focusing on the recently identified disorders caused either by mutations in nuclear genes encoding subunits of the subcomplexes or by mutations in nuclear genes affecting the functional efficiency, homeostasis, and assembly of respiratory chain subcomplexes. To better focus on OXPHOS genotype-phenotype correlations, mutations of the mtDNA-encoded structural genes are also discussed.