Prolotherapy is an injection-based complementary and alternative medical (CAM) therapy for chronic musculoskeletal pain. It has been used for approximately 100 years. Its modern applications, however, can be traced to the 1950s, when the prolotherapy injection protocols were formalized by George Hackett, a general surgeon in the U.S., based on his clinical experience of over 30 years. While prolotherapy techniques and injected solutions vary by condition, clinical severity, and practitioner preferences, a core principle is that a relatively small volume of an irritant or sclerosing solution is injected at sites on painful ligament and tendon insertions, and in adjacent joint space over the course of several treatment sessions. Thus, during an individual prolotherapy session, therapeutic solutions are injected at sites of painful and tender ligament and tendon insertions, and in adjacent joint spaces. Injected solutions (“proliferants”) have historically been hypothesized to cause local irritation, with subsequent inflammation and tissue healing, resulting in enlargement and strengthening of damaged ligamentous, tendon and intra-articular structures. These processes have been observed to improve joint stability, biomechanics, function and ultimately, to decrease pain.