During intense exercise or electrical stimulation of skeletal muscle the concentrations of several ions change simultaneously in interstitial, transverse tubular and intracellular compartments. Consequently the functional effects of multiple ionic changes need to be considered together. A diminished transsarcolemmal K⁺ gradient per se can reduce maximal force in non‐fatigued muscle suggesting that K⁺ causes fatigue. However, this effect requires extremely large, although physiological, K⁺ shifts. In contrast, moderate elevations of extracellular [K⁺] ([K⁺]_o) potentiate submaximal contractions, enhance local blood flow and influence afferent feedback to assist exercise performance. Changed transsarcolemmal Na⁺, Ca²⁺, Cl⁻ and H⁺ gradients are insufficient by themselves to cause much fatigue but each ion can interact with K⁺ effects. Lowered Na⁺, Ca²⁺ and Cl⁻ gradients further impair force by modulating the peak tetanic force–[K⁺]_o and peak tetanic force–resting membrane potential relationships. In contrast, raised [Ca²⁺]_o, acidosis and reduced Cl⁻ conductance during late fatigue provide resistance against K⁺‐induced force depression. The detrimental effects of K⁺ are exacerbated by metabolic changes such as lowered [ATP]_i, depleted carbohydrate, and possibly reactive oxygen species. We hypothesize that during high‐intensity exercise a rundown of the transsarcolemmal K⁺ gradient is the dominant cellular process around which interactions with other ions and metabolites occur, thereby contributing to fatigue.