Defects of mitochondrial metabolism result in a wide variety of human disorders, which can present at any time from infancy to late adulthood and involve virtually any tissue either alone or in combination. Abnormalities of the electron transport and oxidative phosphorylation (OXPHOS) system are probably the most common cause of mitochondrial diseases. Thirteen of the protein subunits of OXPHOS are encoded by mitochondrial DNA (mtDNA) and mutations of this genome are important causes of OXPHOS deficiency. The link between genotype and phenotype with respect to mtDNA mutations is not clear: the same mutation may result in a variety of phenotypes, and the same phenotype may be seen with a variety of different mtDNA mutations. The pathogenesis of mtDNA mutations is unclear although OXPHOS and ATP deficiency, and free radical generation, are thought to contribute to tissue dysfunction. There is now strong evidence for mitochondrial dysfunction in neurodegenerative disorders. In some cases, e.g. Friedreich's ataxia, hereditary spastic paraplegia, this is a result of a mutation of a nuclear gene encoding a mitochondrial protein, whilst in others, e.g. Huntington's disease, amyotrophic lateral sclerosis, the OXPHOS defect is secondary to events induced by a mutation in a nuclear gene encoding a non-mitochondrial protein. In yet a third group, e.g. Parkinson's disease, Alzheimer's disease, the relationship of the mitochondrial defect to aetiology and pathogenesis is unclear.