Prolotherapy involves the injection of nonbiologic solutions, typically at soft tissue attachments and within joint spaces, to reduce pain and improve function in painful musculoskeletal conditions. A variety of solutions have been used; dextrose prolotherapy is the most rigorously studied and is the focus of this review. Although the mechanism of action is not clearly known, it is likely to be multifactorial. Data on effectiveness for temporomandibular dysfunction are promising but insufficient for recommendations. Research on the mechanism of action and clinical effects of dextrose prolotherapy are under way.