Low-level laser therapy (LLLT) has been used to treat a wide spectrum of painful clinical conditions, commencing within a decade of its production by Maiman in 1960. Initial clinical use outstripped comprehension of the mechanisms of its effects. Further confusion arose with the concurrent use of lasers in acupuncture, a different paradigm. Over subsequent decades, as research focused on understanding the direct effects of light on tissue, several mechanisms underlying LLLT analgesia were proposed. These mechanisms include anti-inflammatory effects, neural blockade, stimulation of lymphatic activity, tissue repair, and reduction of muscle spasm. Each of these mechanisms has been studied from subcellular levels to clinical application. The translation and application of these mechanisms from the laboratory to clinical practice is critical to successful outcomes with LLLT. This chapter outlines the painful conditions in which LLLT is used, the mechanisms for its effects, and practical considerations.