Running overuse injuries are typically associated with excessive pronation of the foot during stance. Excessive pronation may impose stress on the extrinsic muscles of the foot leading to injury. Therefore, the purpose of these studies were to examine the roles of these muscles when an external perturbation was employed in the form of varus, neutral, and valgus-wedged shoes. It was hypothesized that running in the valgus shoes would increase eversion (approximating pronation), the net inversion joint moment, activation of the invertor muscles, and the force in these muscles. The first experiment was designed to investigate the kinematic and kinetic responses to running at 3.6 m/s in the varus, neutral, and valgus shoes. This study also reported the EMG profiles of these muscles. The valgus shoes increased maximum eversion and the peak inversion joint moment. The calculation of joint work also demonstrated that there was greater energy absorption in the frontal plane while running in the valgus shoes. This indirectly suggests that the muscles involved in controlling pronation of the foot absorbed more energy when eversion increased, which could be related to injury potential. No significant differences were observed for EMG. Therefore, the increased joint moment may be due to passive mechanisms. The second experiment further investigated the activation of the extrinsic foot muscles using both EMG and functional fMRI during treadmill running. Generally, the activations patterns did not agree with the hypothesis that increased pronation would lead to increased muscle activity. The third study compared joint moments calculated in the frontal plane with joint moments calculated about an estimate of the subtalar joint. This study demonstrated that frontal plane kinetics might give an inaccurate portrayal of the muscular contributions to controlling foot motion. The fourth study developed a musculoskeletal model to estimate the force in each of the extrinsic foot muscles. The model established that the soleus was a substantial contributor to inversion of the foot, along with the tibialis posterior. Also, the valgus shoe increased energy absorption in the soleus tendon. These data may establish a direct link between “excessive” pronation and injuries such as medial tibial stress syndrome.