The recent recognition of the magnitude of cardiovascular risk of both nonselective nonsteroidal anti-inflammatory drugs and COX-2 selective inhibitors, in addition to the persistent concerns about the use of opioids, has brought increased attention to nonsystemic, topical analgesics. These agents have a favorable safety profile and there is increasing evidence indicating their efficacy for a variety of pain disorders. The use of topical analgesics in the treatment of the most prevalent musculoskeletal pain syndromes is described, with a focus on mechanisms for drug delivery and clinical trials data.