Anterior cruciate ligament (ACL) injury is a common and potentially catastrophic knee joint injury, afflicting a large number of males and particularly females annually. Apart from the obvious acute injury events, it also presents with significant long-term morbidities, in which osteoarthritis (OA) is a frequent and debilitative outcome. With these facts in mind, a vast amount of research has been undertaken over the past five decades geared toward characterizing the structural and mechanical behaviors of the native ACL tissue under various external load applications. While these efforts have afforded important insights, both in terms of understanding treating and rehabilitating ACL injuries; injury rates, their well-established sex-based disparity, and long-term sequelae have endured. In reviewing the expanse of literature conducted to date in this area, this paper identifies important knowledge gaps that contribute directly to this long-standing clinical dilemma. In particular, the following limitations remain. First, minimal data exist that accurately describe native ACL mechanics under the extreme loading rates synonymous with actual injury. Second, current ACL mechanical data are typically derived from isolated and oversimplified strain estimates that fail to adequately capture the true 3D mechanical response of this anatomically complex structure. Third, graft tissues commonly chosen to reconstruct the ruptured ACL are mechanically suboptimal, being overdesigned for stiffness compared to the native tissue. The net result is an increased risk of rerupture and a modified and potentially hazardous habitual joint contact profile. These major limitations appear to warrant explicit research attention moving forward in order to successfully maintain/restore optimal knee joint function and long-term life quality in a large number of otherwise healthy individuals.