Mitochondrial DNA (mtDNA) mutations are surprisingly common, with a prevalence of up to 10% in patients with diabetes mellitus, hearing loss, or renal failure. A 36-year-old man with a history of psychosis, seizures, sensorineural hearing loss, and a family history of diabetes mellitus and heart disease had undergone evaluation by primary care physicians for 15 years without a unifying diagnosis. Physiologic, biochemical, and genetic testing established the diagnosis of mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome. Diagnosing mtDNA disorders requires a careful integration of clinical signs and symptoms with pedigree analysis and multidisciplinary testing. Diagnosis is important to provide genetic counseling, avoid unnecessary evaluation, and facilitate therapy for symptomatic relief.