Impaired calcium release from the sarcoplasmic reticulum (SR) has been identified as a contributor to fatigue in isolated skeletal muscle fibers. The functional importance of this phenomenon can be quantified by the use of agents, such as caffeine, which can increase SR Ca(2+) release during fatigue. A number of possible mechanisms for impaired calcium release have been proposed. These include reduction in the amplitude of the action potential, potentially caused by extracellular K(+) accumulation, which may reduce voltage sensor activation but is counteracted by a number of mechanisms in intact animals. Reduced effectiveness of SR Ca(2+) channel opening is caused by the fall in intracellular ATP and the rise in Mg(2+) concentrations that occur during fatigue. Reduced Ca(2+) available for release within the SR can occur if inorganic phosphate enters the SR and precipitates with Ca(2+). Further progress requires the development of methods that can identify impaired SR Ca(2+) release in intact, blood-perfused muscles and that can distinguish between the various mechanisms proposed.