Skeletal muscle fatigue develops gradually during all forms of exercise, and develops more rapidly in heart failure patients. The fatigue mechanism is still not known, but is most likely localized to the muscle cells themselves. During high intensity exercise the perturbations of the Na+ and K+ balance in the exercising muscle favour depolarization, smaller action potentials and inexcitability. The Na+, K+ pump becomes strongly activated and limits, but does not prevent the rise in extracellular Na+, K+ pump concentration and intracellular Na+ concentration. However, by virtue of its electrogenic property the pump may contribute in maintaining excitability and contractility by keeping the cells more polarized than the ion gradients predict. With prolonged exercise perturbations of Na+ and K+ are smaller and fatigue may be associated with altered cellular handling of Ca2+ and Mg2+. Release of Ca2+ from the sarcoplasmic reticulum (SR) is reduced in the absence of changes of the cellular content of Ca2+ and Mg2+. In heart failure several clinical reports indicate severe electrolyte perturbations in skeletal muscle. However, in well controlled studies small or insignificant changes are found. We conclude that with high intensity exercise perturbations of Na+ and K+ in muscle cells may contribute to fatigue, whereas with endurance type of exercise and in heart failure patients the skeletal muscle fatigue is more likely to reside in the intracellular control of Ca2+ release and reuptake.