Computational modeling has been used for many decades to inform design and decision-making in several fields of engineering, such as aerospace, automotive, petroleum, and others. However, it still struggles to have a similar impact in fields of medicine, such as orthopaedics. Three of the challenges that have limited the use of computational modeling in the clinical practice and in product development are model validation, personalization, and realism. Validation is a challenge because several internal parameters of the human body, such as muscle forces, are not safely measurable in vivo and, consequently, a thorough comparison between model outputs and experimental measurements is not always possible. Personalization is an additional issue because the inherent variability across a population needs to be accounted for in a model. Finally, the computational burden of simulations performed with a musculoskeletal model limits its level of realism. The purpose of the work presented in this dissertation is to investigate the applicability of state-of-the-art tools, and propose novel approaches to foster an evolution of computational modeling in orthopaedics. Specifically, (1) the reliability of the knee contact force predictions of a musculoskeletal model commonly used in the literature was analyzed using a global probabilistic analysis for three subjects with instrumented implants; (2) subject-specific and activity-specific moment arms of the muscles spanning the knee were estimated replacing the generic passive cadaveric motion implemented in the knee joint of a musculoskeletal model with in vivo kinematics measured from stereoradiography images; (3) subject-specific joint mechanics for 6 total knee arthroplasty patients performing daily activities was estimated with a sequential multiscale modeling approach that combined joint loads estimated with a whole body musculoskeletal model, personalized joint geometries, and subject-specific fluoroscopy-measured kinematics; finally, (4) a closed-loop muscle control strategy was designed to track experimental joint kinematics and concurrently estimate muscle forces and knee mechanics with a finite element musculoskeletal model of the lower limb including a deformable representation of the joint. The utility of the modeling techniques proposed in this dissertation is presented within a clinical perspective in order to encourage the utilization of musculoskeletal modeling for clinical applications and product development.