Prolotherapy is an injection-based treatment that seeks to induce tissue healing and repair through the introduction of irritating solutions into soft tissue structures. Modern practice of prolotherapy is conventionally aimed at addressing various musculoskeletal complaints including pain, instability, and laxity attributable to either overt or microtrauma within supporting connective tissue structures. Prolotherapy is distinct from other regenerative techniques in that its injectate lacks a biologic agent. Mild-to-moderate evidence exists for the use of hyperosmolar dextrose solutions to address ligamentous injuries, osteoarthritis, and tendinopathy; however, injection protocols are heterogenous, and a unifying consensus on best practice for various conditions has not yet been established.