Repeated activation of skeletal muscle causes fatigue, which involves a reduced ability to produce force and slowed contraction regarding both the speed of shortening and relaxation. One important component in skeletal muscle fatigue is a reduced sarcoplasmic reticulum (SR) Ca²⁺ release. In the present review we will describe different types of fatigue-induced inhibition of SR Ca²⁺ release. We will focus on a type of long-lasting failure of SR Ca²⁺ release which is called low-frequency fatigue, because this type of fatigue may be involved in the muscle dysfunction and chronic pain experienced by computer workers. Paradoxically it appears that the Ca²⁺ released from the SR, which is required for contraction, may actually be responsible for the failure of SR Ca²⁺ release during low-frequency fatigue. We will also discuss the relationship between gross morphological changes in muscle fibres and long-lasting failure of SR Ca²⁺ release. Finally, a model linking muscle cell dysfunction and muscle pain is proposed.