© 2014 Elsevier Inc. All rights reserved. The mitochondrial respiratory chain is important for generating cellular energy and, therefore, dysfunction of this process plays an important role in human disease. Consideration of the functional components of the electrochemical gradient comprising the respiratory chain provides the basis for identifying the cause of the multisystem diseases that arise from mitochondrial abnormalities. Diagnosis may depend on the pattern of inheritance, whether Mendelian or maternal, based on mitochondrial or nuclear DNA. Diagnosis relies on biochemical and molecular analyses, neuroimaging, or histological findings. The classification of such disorders may include abnormalities of uncoupled oxidative phosphorylation, translocation of respiratory chain metabolites, defective protein assembly, abnormal intramitochondrial metal homeostasis, and specific neurodegenerative disorders. Therapy is generally ineffective, although combination of various vitamins have occasionally been helpful. Genetic therapies are being actively pursued.