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In this paper, we review a series of studies that we initiated to examine mechanisms of anterior cruciate ligament (ACL) injury in the hope that these injuries, and their sequelae, can be better prevented. First, using the earliest in vitro model of a simulated single‐leg jump landing or pivot cut with realistic knee loading rates and trans‐knee muscle forces, we identified the worst‐case dynamic knee loading that causes the greatest peak ACL strain: Combined knee compression, flexion, and internal tibial rotation. We also identified morphologic factors that help explain individual susceptibility to ACL injury. Second, using the above knee loading, we introduced a possible paradigm shift in ACL research by demonstrating that the human ACL can fail by a sudden rupture in response to repeated sub‐maximal knee loading. If that load is repeated often enough over a short time interval, the failure tended to occur proximally, as observed clinically. Third, we emphasize the value of a physical exam of the hip by demonstrating how limited internal axial rotation at the hip both increases the susceptibility to ACL injury in professional athletes, and also increases peak ACL strain during simulated pivot landings, thereby further increasing the risk of ACL fatigue failure. When training at‐risk athletes, particularly females with their smaller ACL cross‐sections, rationing the number and intensity of worst‐case knee loading cycles, such that ligament degradation is within the ACL's ability to remodel, should decrease the risk for ACL rupture due to ligament fatigue failure.© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2059–2068, 2016.

New perspectives on ACL injury: On the role of repetitive sub‐maximal knee loading in causing ACL fatigue failure