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Intensive activity of muscles causes a decline in performance, known as fatigue, that is thought to be caused by the effects of metabolic changes on either the contractile machinery or the activation processes. The concentration of inorganic phosphate (Pi) in the myoplasm ([Pi]myo) increases substantially during fatigue and affects both the myofibrillar proteins and the activation processes. It is known that a failure of sarcoplasmic reticulum (SR) Ca2+ release contributes to fatigue and in this review we consider how raised [Pi]myo contributes to this process. Initial evidence came from the observation that increasing [Pi]myo causes reduced SR Ca2+ release in both skinned and intact fibres. In fatigued muscles the store of releasable Ca2+ in the SR declines mirroring the decline in SR Ca2+ release. In muscle fibres with inoperative creatine kinase the rise of [Pi]myo is absent during fatigue and the failure of SR Ca2+ release is delayed. These results can all be explained if inorganic phosphate can move from the myoplasm into the SR during fatigue and cause precipitation of CaPi within the SR. The relevance of this mechanism in different types of fatigue in humans is considered.