AbstractCells and tissue within injured organs undergo a complicated healing process that still remains poorly understood. Interestingly, smaller organisms respond to injury with tissue regeneration and restoration of function, while humans and other large organisms respond to injury by forming dysfunctional, fibrotic scar tissue. Over the past few decades, allometric scaling principles have been well established to show that larger organisms experience exponentially higher tissue forces during movement and locomotion and throughout the organism's lifespan. How these evolutionary adaptations may affect tissue injury has not been thoroughly investigated in humans. We discuss how these adapations may affect healing and demonstrate that blocking the most evolutionary conserved biologic force sensor enables large organisms to heal after injury with true tissue regeneration. Future strategies to disrupt tissue force sensors may unlock the key to regenerating after injury in a wide range of organ systems.