This chapter is based on the premise that treatment with prolotherapy can greatly reduce chronic musculoskeletal pain, which affects more than 1 billion people worldwide. Although relatively unknown to mainstream medicine, prolotherapy has been used for decades to treat chronic musculoskeletal pain, doing so by correcting the underlying cause of that pain: joint instability due to ligament laxity. Discussions of joint instability, ligament physiology and biomechanics, compressive and shear forces, sites of instability, pain referral patterns, and ligament injury and healing demonstrate how they all interrelate to cause chronic pain. Treating chronic pain using nonsteroidal anti-inflammatory drugs, corticosteroids, and the rest, ice, compression, and elevation protocol actually inhibit the natural healing process of injured ligaments because they interrupt the inflammatory response, prevent joint swelling, and hinder cell proliferation, resulting in further ligament laxity and tissue regrowth that is inferior to native ligament tissue. Unlike conventional treatments, prolotherapy injects small volumes of an irritant solution into painful ligaments, tendons, joints, and surrounding joint spaces, initiating an inflammatory response which then attracts substances that promote normal cell and tissue growth. Their propagation stimulates the injured ligament to proliferate and grow at the injection sites, resulting in the regeneration of new tissue.