More than 250,000 anterior cruciate ligament (ACL) injuries occur each year in the USA, and approximately 65% of these injuries undergo reconstructive surgery. Appropriate rehabilitation after ACL reconstruction can yield predictably good outcomes, with return to previous levels of activity and high knee function. At present, periodization is used at all levels of sports training. Whether conceptualized and directed by coaches, or by athletes themselves, competitors structure their training in a cyclic fashion, enabling athletes to best realize their performance goals. In practical application, sport physical therapists use periodization: postoperative “protocols” serve as rudimentary forms of periodization, albeit implemented over shorter time frames than that typically employed in preparation for competition. An ACL injury should not be considered a “simple” musculoskeletal pathology with only local mechanical or motor dysfunctions. Together with the psychological trauma and reduction in physical capacity, there is a cascade of events, including neurological insult to the central nervous system and reduction in afferences to the sensorimotor system. Rehabilitation should consider all these issues, and periodization would allow to better define and to plan aims and objectives to return athletes to their sport. Technological resources including advanced neuroimaging methods, virtual reality for injury risk screening and return to sport assessment, and interactive artificial reality-based neuromuscular training methods offer new approaches and tools to address this important biomedical problem. The cost and availability of many of these technologies will continue to decrease, providing greater availability, scientific rigor, and ultimately, utility for cost-effective and data-driven assessments.