Mitochondrial encephalomyopathies are diseases caused by defective oxidative phosphorylation (OXPHOS), and affect the nervous system and/or skeletal muscle. They have emerged as a major entity among the neurometabolic diseases of childhood with an incidence of 1 in 11,000 children, and also have a high prevalence in adults. The first pathogenic mutation of human mitochondrial DNA (mtDNA) was discovered in 1988. Since then more than 100 mutations of mtDNA have been reported, including point mutations of genes encoding transfer RNA, ribosomal RNA, and proteins, as well as large-scale deletions. The first nuclear-DNA gene mutation causing OXPHOS disease was described in 1995. Mutations in nuclear genes may affect the respiratory chain by various mechanisms. Pathogenic mutations of nuclear-DNA-encoded subunits of complex I and II have been demonstrated as have mutations of respiratory chain assembly proteins. Several nuclear genes associated with mtDNA maintenance have been found to be associated with mitochondrial disorders since mutations in these genes predispose to multiple mtDNA deletions and/or reduced copy number of mtDNA. The genotype-phenotype correlation is not yet entirely clear, but new animal models will enhance our ability to study the pathophysiology of OXPHOS disorders.