Background: The onset and progression of osteoarthritis, but also the wear and loosening of the components of an artificial joint, are commonly associated with mechanical overloading of the structures. Knowledge of the mechanical forces acting at the joints, together with an understanding of the key factors that can alter them, are critical to develop effective treatments for restoring joint function. While static anatomy is usually the clinical focus, less is known about the impact of dynamic factors, such as individual muscle recruitment, on joint contact forces. Methods: In this study, instrumented knee implants provided accurate in vivo tibio-femoral contact forces in a unique cohort of 9 patients, which were used as input for subject specific musculoskeletal models, to quantify the individual muscle forces during walking and stair negotiation. Results: Even between patients with a very similar self-selected gait speed, the total tibio-femoral peak forces varied 1.7-fold, but had only weak correlation with static alignment (varus/valgus). In some patients, muscle co-contraction of quadriceps and gastrocnemii during walking added up to 1 bodyweight (~50%) to the peak tibio-femoral contact force during late stance. The greatest impact of co-contraction was observed in the late stance phase of stair ascent, with an increase of the peak tibio-femoral contact force by up to 1.7 bodyweight (66%). Conclusions: Treatment of diseased and failed joints should therefore not only be restricted to anatomical reconstruction of static limb axes alignment. The dynamic activation of muscles, as a key modifier of lower limb biomechanics, should also be taken into account and thus also represents a promising target for restoring function, patient mobility, and preventing future joint failure. Trial registration: German Clinical Trials Register: ID: DRKS00000606, date: 05.11.2010.