Leigh syndrome or subacute necrotizing encephalomyelopathy was first recognised as a neuropathological entity in 1951. It is a progressive neurological disease characterised by neuroradiological lesions, particularly in the brainstem and basal ganglia. Leigh's syndrome is a pan-ethnic disorder with onset usually in infancy or early childhood. Over the last six decades, this complex neurodegenerative disorder has been shown to comprise more than 100 separate monogenic disorders associated with enormous clinical and biochemical heterogeneity. This article reviews clinical, radiological, biochemical and genetic aspects of the disorder. Leigh syndromes present with childhood developmental regression, a loss of previously achieved developmental milestones. Numerous non-neurological manifestations of Leigh syndrome have been reported, many of which are related to the underlying genetic defects. These include cardiomyopathy, renal tubulopathy, gastrointestinal and endocrine dysfunction, and liver disease. Known genetic causes, including defects in 16 mitochondrial DNA (mtDNA) genes and nearly 100 nuclear genes, are categorised into disorders of subunits and assembly factors of the five oxidative phosphorylation enzymes, disorders of pyruvate metabolism and vitamin and cofactor transport and metabolism, disorders of mtDNA maintenance, and defects in mitochondrial gene expression, protein quality control, lipid remodelling, dynamics and toxicity. An approach to diagnosis is presented, together with known treatable causes and an overview of current supportive management options and emerging therapies on the horizon.