It is well established that muscle fatigue, defined as a decline in maximal force generating capacity, is a common response to muscular activity. To what extent metabolic factors contribute to the reduced muscle function is still debated. Metabolic effects can affect muscle through different processes, either through a reduced ATP supply or by effects on EC-coupling or crossbridge dynamics. Observations from in vitro experiments are often extrapolated to interpret fatigue mechanisms from measurements performed in vivo, without recognizing that the biochemical reactions involved can be quite different depending on such factors as activation pattern, mode and duration of exercise. During repeated submaximal contractions, there is a negligible accumulation of H+ and inorganic phosphate, and hence fatigue must be ascribed to other factors. Substrate depletion might contribute to exhaustion, but cannot explain the gradual loss of maximal force. Curiously, the energetic cost of contraction increases progressively during repeated isometric but not during concentric contractions. With contractions involving high-force or high power output, fatigue is better related to H2PO4- than to pH, but still other factors seem to play a role.