The integrity of the human musculoskeletal system can be compromised with excessive and/or abnormal loading during dynamic activities. Knee osteoarthritis (OA), the progressive degeneration of the knee joint, has been particularly associated with mechanical factors during gait and is one of the main causes of disability across the world. Modern gait analysis is an established method of measuring the mechanical and neuromuscular factors of knee OA, but commonly used inverse dynamics modeling with gait data calculates only net resultant forces and moments at a joint, not accounting for force contributions from muscles spanning the joint. Reported joint forces are therefore conceptual quantities that are not necessarily physically present in any single joint structure. To understand the destructive pathways of knee OA and other diseases of the musculoskeletal system, it is important to determine accurate joint contact forces. This can be achieved by combining gait and electromyography data with more sophisticated modeling and optimization techniques that incorporate behavioral muscle models and more specific joint anatomy. Further, subject-specific musculoskeletal modeling and simulation can combine variations in joint geometry, alignment, muscle activation patterns, and lower limb dynamics to determine the unique biomechanical response of an individual. This will allow biomechanical information to be presented in a more specific, clinically-relevant manner than commonly reported generalized patterns. Simulations of the effects of both conservative and surgical interventions on the models will also provide an efficient and ethical manner of tailoring treatment strategies to an individual.