ABSTRACTDaily activities subject our tendons to accumulation of sub‐rupture fatigue injury which can lead to tendon rupture. Consequently, tendinopathies account for over 30% of musculoskeletal consultations. We adopted a multidisciplinary approach to determine the role of the extracellular matrix (ECM) in the pathogenesis of tendinopathy and impaired healing of ruptured tendons. We have been investigating three main areas: (i) the pathogenesis of tendon degeneration; (ii) approaches to promoting remodeling of sub‐rupture fatigue injuries; and the (iii) role of the ECM in promoting scarless tendon healing. In this Kappa Delta Young Investigator award paper, we describe the key discoveries made in each of our three research areas of focus. Briefly, we discovered that sub‐rupture fatigue damage can accumulate from just one bout of fatigue loading. Furthermore, any attempt to repair the fatigue damage diminishes as the severity of induced damage increases. We have utilized exercise to develop animal models of exercise‐led degeneration and exercise‐led repair of sub‐rupture fatigue damage injuries, wherein underlying mechanisms can be uncovered, thereby overcoming a major hurdle to development of therapeutics. Since damage accumulation ultimately leads to rupture that is characterized by formation of a mechanically inferior scar, we have used the MRL/MpJ mouse to evaluate the role of the systemic environment and the local tendon environment in driving regeneration to identify new therapeutic pathways to promote scarless healing. Our data suggests that the therapeutic potential of the MRL/MpJ provisional ECM should be further explored as it may harness biological and structural mechanisms to promote scarless healing. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3115–3124, 2018.