Intracellular acidosis caused by lactic acid formation and the accumulation of inorganic phosphate (Pi) by phosphocreatine(PCr) breakdown were regarded to be major factors in the process of muscle fatigue. However, recent studies on skinned and intact isolated mammalian muscle fibres at physiological temperatures have only shown minor effects of physiologically low pH values on contractility. However, physiologically high concentrations of phosphate seem to reduce force and shortening velocity by a direct inhibition of cross-bridge cycling and by a reduction in Ca- release from SR. Recent in-vivo studies using 31 P MRS on human skeletal muscle seem to support these findings. During 10 intervals of 15 s intense dynamic exercise, contraction velocity of the calf muscle significantly fell by about 30% within each interval. A deep PCr depletion and the correspondig increase in Pi caused an alkalinization by about 0.3 units. Acidification only occured during the 45s long recovery periods. Incomplete recovery of PCr and Pi corresponded with a reduced initial contraction velocity from the 2nd to the 10th contraction interval. In patients with myo-phosphorylase deficiency fatigue at moderate long term load also corresponds with a distinc alkalinisation and a steep Pi accumulation. In vivo studies clearly show that acidification is not a cause of skeletal muscle fatigue during high intense exercise. Phosphates always accumulates to levels which inhibit contractility in experiments on isolated fibres.