Defects of the mitochondrial genome are increasingly being recognised as important causes of disease. Patients may present at any age and the symptoms vary from fatal lactic acidosis in infancy to muscle disease in adults. For most patients there is no satisfactory treatment and there is a gradual deterioration leading to severe disability and death. In the absence of any biochemical treatment, gene therapy must be considered for these patients. This review addresses the unique problems associated with the treatment of defects of the mitochondrial genome by gene therapy, and discusses the approaches which we believe may be of value.