The pivotal role of biomechanics in the past 50 years in consolidating the basic knowledge that underpins prevention and rehabilitation measures has made this area a great spotlight for health practitioners. In clinical practice, biomechanics analysis of spatiotemporal, kinematic, kinetic, and electromyographic data in various chronic conditions serves to directly enhance deeper understanding of locomotion and the consequences of musculoskeletal dysfunctions in terms of motion and motor control. It also serves to propose straightforward and tailored interventions. The importance of this approach is supported by myriad biomechanical outcomes in clinical trials and by the development of new interventions clearly grounded on biomechanical principles. Over the past five decades, therapeutic interventions have been transformed from fundamentally passive in essence, such as orthoses and footwear, to emphasizing active prevention, including exercise approaches, such as bottom-up and top-down strengthening programs for runners and people with osteoarthritis. These approaches may be far more effective in reducing pain, dysfunction, and, ideally, incidence if they are based on the biomechanical status of the affected person. In this review, we demonstrate evidence of the impact of biomechanics and motion analysis as a foundation for physical therapy/rehabilitation and preventive strategies for three chronic conditions of high worldwide prevalence:​ diabetes and peripheral neuropathy, knee osteoarthritis, and running-related injuries. We conclude with a summary of recommendations for future studies needed to address current research gaps.