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Recent studies have examined alternative treatment methods, including repair and regeneration of the injured ligament. In order to make such an approach feasible, a basic understanding of ACL biology and its response to injury is needed. Identification of obstacles to native ACL healing can then be identified and potentially resolved using tissue engineering strategies\u2014first, with in vitro screening assays, and then with in vivo models of efficacy and safety. This Perspectives paper outlines this path of discovery for optimizing ACL healing using a bio\u2010enhanced repair technique. This journey required constructing indices of the functional tissue response, pioneering physiologically based methods of biomechanical testing, developing, and validating clinically relevant animal models, and creating and optimizing translationally feasible scaffolds, surgical techniques, and biologic additives. Using this systematic translational approach, \u201cbio\u2010enhanced\u201d ACL repair has been advanced to the point where it may become an option for future treatment of acute ACL injuries and the prevention of subsequent post\u2010traumatic osteoarthritis associated with this injury. \u00a9 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. 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