The physical demands in soccer have been studied intensively, and the aim of the present review is to provide an overview of metabolic changes during a game and their relation to the development of fatigue. Heart-rate and body-temperature measurements suggest that for elite soccer players the average oxygen uptake during a match is around 70% of maximum oxygen uptake (VO2max). A top-class player has 150 to 250 brief intense actions during a game, indicating that the rates of creatine-phosphate (CP) utilization and glycolysis are frequently high during a game, which is supported by findings of reduced muscle CP levels and severalfold increases in blood and muscle lactate concentrations. Likewise, muscle pH is lowered and muscle inosine monophosphate (IMP) elevated during a soccer game. Fatigue appears to occur temporarily during a game, but it is not likely to be caused by elevated muscle lactate, lowered muscle pH, or change in muscle-energy status. It is unclear what causes the transient reduced ability of players to perform maximally. Muscle glycogen is reduced by 40% to 90% during a game and is probably the most important substrate for energy production, and fatigue toward the end of a game might be related to depletion of glycogen in some muscle fibers. Blood glucose and catecholamines are elevated and insulin lowered during a game. The blood free-fatty-acid levels increase progressively during a game, probably reflecting an increasing fat oxidation compensating for the lowering of muscle glycogen. Thus, elite soccer players have high aerobic requirements throughout a game and extensive anaerobic demands during periods of a match leading to major metabolic changes, which might contribute to the observed development of fatigue during and toward the end of a game.