Traditional methods employed to study musculoskeletal injury mechanisms and joint biomechanics utilize in vivo or in vitro techniques. The advent of new technology and improved methods has also given rise to in silico (computer modeling) techniques. Under the current research paradigm, in vivo, in vitro, and in silico methods independently provide information regarding the mechanisms and prevention of musculoskeletal injury. However, individually, each of these methods have multiple, inherent limitations and are likely to provide incomplete answers about multi-factorial, complex injury conditions. The purpose of this treatise is to review current methods used to study, understand, and prevent musculoskeletal injury and to develop new conceptual-methodological frameworks that may help create a paradigm shift in musculoskeletal injury prevention research. We term the fusion of these three techniques in simulacra amalgama, or simply in sim meaning a “union of models done on the likeness of phenomena.” ACL injury will be employed as a model example for the utility and applicability of the proposed, synthesized approach. Shifting the current experimental paradigm to incorporate a multi-faceted, multi-disciplinary, integration of in vivo, in vitro, and in silico methods into the proposed in sim approaches may provide a platform for a more comprehensive understanding of the relationships between complex joint biomechanics and observed injury mechanisms.