Therapy for mitochondrial diseases is woefully inadequate. However, lack of a cure does not equate with lack of treatment. Palliative therapy is dictated by good medical practice and includes anticonvulsant medication, control of endocrine dysfunction, and surgical procedures. Removal of noxious metabolites is centered on combating lactic acidosis, but extends to other metabolites. Attempts to bypass blocks in the respiratory chain by administration of electron acceptors have not been successful, but this may be amenable to genetic engineering. Administration of metabolites and cofactors is the mainstay of real-life therapy and is especially important in disorders due to primary deficiencies of specific compounds, such as carnitine or coenzyme Q10 (CoQ10). There is increasing interest in the administration of reactive oxygen radicals (ROS) scavengers, both in primary mitochondrial diseases and in neurodegenerative diseases. Gene therapy is a challenge because of polyplasmy and heteroplasmy, but novel experimental approaches are being pursued. One important strategy is to decrease the ratio of mutant to wild-type mitochondrial genomes ("gene shifting") by different means: (1) converting mutated mitochondrial DNA (mtDNA) genes into normal nuclear DNA genes ("allotopic expression"); (2) importing cognate genes from other species ("xenotopic expression"); (3) correcting mtDNA mutations by importing specific restriction endonucleases; (4) selecting for respiratory function; and (5) inducing muscle regeneration. Germline therapy raises ethical problems but is being considered for prevention of maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is becoming increasingly important for nuclear DNA-related disorders.