Metatarsal stress fractures occur in military recruits after long marches and in athletes after episodes of overtraining involving running or jumping. It has been demonstrated that contraction of the plantar flexors of the toes helps to counteract the moments placed on the metatarsals by body weight. It is possible that physiological fatigue due to strenuous or repetitive exercise reduces the rate and force of contraction of the plantar flexors, thereby increasing metatarsal strain per cycle, and that this mechanism is the primary cause of stress fractures of these bones. To test the hypothesis that fatigue of the plantar flexors causes increased metatarsal loading, thereby predisposing these bones to stress fracture, we measured metatarsal strains in nine fresh cadaveric feet with use of an apparatus that simulated physiological loading due to body weight as well as contraction of the plantar flexors. Each foot was loaded to 750 newtons of ground-reaction force by simulated contraction of the triceps surae, and strains were recorded in the mid-part of the shaft of the second metatarsal. Tests were repeated with use of simulated activity of different combinations of the flexor digitorum longus, flexor hallucis longus, peroneus brevis, peroneus longus, and tibialis posterior muscles. In situ bending moments and axial loads subsequently were derived for each configuration. Dorsal strain was significantly reduced by simulated contraction of the flexor hallucis longus. Plantar-dorsal bending was significantly reduced by simulated contraction of the flexor digitorum longus.