Fatigue of skeletal muscle involves many systems beginning with the central nervous system and ending with the contractile machinery. This review concentrates on those factors that directly affect the actomyosin interaction: the build-up of metabolites; myosin phosphorylation; and oxidation of the myofibrillar proteins by free radicals. The decrease in [ATP] and increase in [ADP] appear to play little role in modulating function. The increase in phosphate inhibits tension. The decrease in pH, long thought to be a major factor, is now known to play a more minor role. Myosin phosphorylation potentiates the force achieved in a twitch, and a further role in inhibiting velocity is proposed. Protein oxidation can both potentiate and inhibit the actomyosin interaction. It is concluded that these factors, taken together, do not fully explain the inhibition of the actomyosin interaction observed in living fibers, and thus additional modulators of this interaction remain to be discovered.