Skeletal muscles induced to contract repeatedly respond with a progressive loss in their ability to generate a target force or power. This decline in function, referred to as muscle fatigue, has a complex etiology that can involve various metabolic and ionic factors. Of these, intracellular acidosis due to lactic acid accumulation has been regarded as one of the important causes of muscle fatigue that occurs with intense exercise. Recent surveys, however, have demonstrated little direct effect of acidosis on muscle function at physiological temperatures, and in fact several putative mechanisms by which intracellular changes can attenuate contractile function have been proposed. The most likely mechanisms to explain muscle fatigue include elevated inorganic phosphate concentrations that result from phosphocreatine breakdown, compartmentalized depletion of endogenous muscle glycogen and/or modification by reactive oxygen species that are produced extensively in contracting muscle fibers. This brief review seeks to examine how these three alterations contribute to muscular fatigue processes.