Background: Iliotibial band syndrome (ITBS) is the leading cause of lateral knee pain in runners. Previous research has theorized that higher ITB strain rate leads to ITBS development. Orthotics are commonly used to correct gait mechanics and may reduce ITB strain and strain rate. The purpose of this research was to investigate how wedge inserts and gender affect kinematics, kinetics, and ITB strain and strain rate during running. Methods: Thirty (15 male, 15 female) participants ran with lateral 7°, lateral 3°, no wedge, medial 3°, and medial 7° wedges. A motion capture system and force platform were used to collect kinematic and kinetic data. Joint angles and joint moments were calculated during the stance phase. ITB strain and strain rate were determined using a six degree of freedom musculoskeletal model. Findings: There were no significant differences for ITB strain or strain rate between wedge conditions or genders. The lateral 7° wedge resulted in significantly higher ankle eversion angles and lower ankle plantar flexion moments than no wedge. The medial 7° wedge resulted in significantly lower ankle eversion angles, higher hip internal rotation angles, lower ankle plantar flexion moments, lower ankle inversion moments, and higher external knee varus moments. Males had significantly higher knee valgus angles, knee internal rotation angles, ankle plantar flexion moments, ankle inversion moments, and knee extension moments. Interpretation: Results indicate that wedge inserts do not have a significant effect upon ITB strain and strain rate for healthy runners. While wedge orthotics may correct ankle/foot alignment problems, higher external knee varus moments with a medial 7° wedge are of concern.