Patients with mitochondrial cytopathies often experience exercise intolerance and may have fixed muscle weakness, leading to impaired functional capacity and lower quality of life. Endurance exercise training increases Vo2max, respiratory chain enzyme activity, and improves quality of life. Resistance exercise training increases muscle strength and may lower mutational burden in patients with mitochondrial DNA deletions. Both modes of exercise appear to be well tolerated. Patients with mitochondrial cytopathy should consider alternating both types of exercise to derive the benefits from each (endurance = greater aerobic fitness; resistance = greater strength). Patients should start an exercise program at a low intensity and duration, gradually increasing duration and intensity. They should “listen to their body” and not exercise on days they have fever, superimposed illness, muscle pain, or cramps, and/or if they have fasted for more than 12 hours. Children often respond best to play-based exercise and tend to enjoy intermittent activity.