Prolonged dynamic exercise and sustained isometric contractions induce muscle fatigue, as manifested by decreased performance and a reduction in the maximum voluntary contraction force. Studies with non-invasive measurements in exercising humans show that mechanisms located beyond the sarcolemma are important in the fatigue process. In this review, we describe probable cellular mechanisms underlying fatigue-induced changes in excitation-contraction (E-C) coupling occurring in human muscle fibres during strenuous exercise. We use fatigue-induced changes observed in intact single muscle fibres, where force and cellular Ca(2+) handling can be directly measured, to explain changes in E-C coupling observed in human muscle during exercise.