the habitual motion path theory predicts that humans tend to maintain their habitual motion path (HMP) during locomotion. The HMP is the path of least resistance of the joints defined by an individual's musculoskeletal anatomy and passive tissue properties. Here we tested whether participants with higher HMp deviation and whether using footwear that increases HMp deviation during running show higher reductions of knee joint articular cartilage volume after 75 minutes of running. We quantified knee joint articular cartilage volumes before and after the run using a 3.0-Tesla MRI. We performed a 3D movement analysis of runners in order to quantify their HMP from a two-legged squat motion and the deviation from the HMP when running in different footwear conditions. We found significantly more cartilage volume reductions in the medial knee compartment and patella for participants with higher HMp deviation. We also found higher cartilage volume reductions on the medial tibia when runners wore a shoe that maximized their HMp deviation compared with the shoe that minmized their HMp deviation. Runners might benefit from reducing their HMP deviation and from selecting footwear by quantifying HMP deviation in order to minimize joint cartilage loading in sub-areas of the knee.Overuse injuries in distance running occur with gradual onset over time and result from the repetitive stress of biological tissues and associated cumulative trauma 1 . The knee joint is the most common site for running-related overuse injuries (RROIs) 2 . Nigg et al. have proposed that the neural control of running is tuned towards minimizing mechanical stress of biological tissues, resulting in an optimal path of lower extremity joint movement for each individual and every specific movement 3 . Recently, we proposed a redefinition of this theory by assuming that the neural control of running is tuned towards keeping the individual's habitual joint motion path (HMP), which we define as the joints' path of least resistance, and a function of an individual's anatomy and passive tissue mechanical properties 4 . As such, the HMP is the set of joint kinematics during motions which minimizes loading of lower extremity joints relative to the loads during running. Examples for these relatively low loading motions are walking, stair climbing, sitting down or standing up from a chair. Consequently, we have developed a simple method to estimate the HMP for individuals from a basic half-squat movement 4 .Running at typical distance running speeds requires greater force application to the ground in order to satisfy the body weight support requirement during shorter ground contact times compared to walking 5,6 . Therefore, runners must generate amplified lower extremity joint moments when running in order to maintain the HMP and to optimize the load distribution to regions that have been adapted to carry these loads. Based on the HMP theory, deviating from the HMP leads to loading of less adapted structures of lower extremity joints, resulting in a greater risk of s...