Because of the bi-genomic origin of the OXPHOS system, mitochondrial disease-associated mutations have been found in both mtDNA and nuclear structural genes. In the last years, interest has shifted toward mendelian genetics in mitochondrial disease, not only because the majority of the OXPHOS system subunits are encoded by the nuclear genome, but also because a large number of yet unknown nuclear proteins, such as regulatory proteins and assembly factors, are likely involved in its biogenesis and function. A clinical-genetic classification can be proposed for nuclear defects that affect the biogenesis of the OXPHOS system, as follows: (i) disorders due to nuclear gene defects encoding structural components or assembly factors of the OXPHOS complexes, (ii) disorders due to gene defects in the biogenesis of protein constituents of the OXPHOS system, (iii) disorders due to defects in the biosynthesis of non-protein constituents of the respiratory chain, and (iv) disorders due to gene defects encoding proteins involved in mitochondrial dynamics.