The performance of skeletal muscles depends on their ability to initiate and propagate action potentials along their outer membranes in response to motor signals from the central nervous system. This excitability of muscle fibres is related to the function of Na+ and K+ and Cl- channels and to steep chemical gradients for the ions across the cell membranes, i.e., the sarcolemma and T-tubular membranes. At rest, the chemical gradients for Na+ and K+ are maintained within close limits by the action of the Na+-K+ pump. During contractile activity, however, the muscles lose K+, which causes an increase in the concentration of K+ in the extracellular compartments of the body, the magnitude of which depends on the intensity of the exercise and the size of the muscle groups involved. Since the ensuing reduction in the chemical K+ gradient can have adverse effects on muscle excitability, it has repeatedly been suggested that, during intense exercise, the loss of K+ from muscle fibres can contribute to the complex set of mechanisms that leads to the development of muscle fatigue. In this review, aspects of the regulation of Na+-K+ homeostasis and excitability in contracting muscles is discussed within this context, together with the implications for the contractile function of skeletal muscles.