Mitochondria have a key role in skeletal muscle in that they decide the oxidative capacity, and hence the fatigue resistance of muscle fibres. Mitochondria also affect the general status of muscle fibres, e.g. by altering gene transcription and by inducing apoptotic signalling. Recent studies from our laboratory show that Ca²⁺ plays an important role in the interaction between mitochondria and general cell function. In this context the concentration and location of Ca²⁺ is critical for the physiological effects. On the hand, we have observed that a minor increase in the Ca²⁺ leak from the sarcoplasmic reticulum (SR), resulting in increased basal Ca²⁺ concentration in the cytosol, is accompanied by increased mitochondrial biogenesis and increased fatigue resistance. On the other hand, results from muscle fibres of mitochondrial myopathy show that increased Ca²⁺ concentration in the mitochondria is accompanied by decreased SR Ca²⁺ content and muscle weakness. These complex Ca²⁺-dependent interactions will be discussed.