Topical drug delivery may be the optimal route for the treatment of localized musculoskeletal disorders because higher drug concentrations can be achieved at the sites of clinical significance. The rationale for the use of topical salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of soft-tissue rheumatic complaints and osteoarthritis is reviewed. Topical capsaicin offers another potentially beneficial therapy for the treatment of osteoarthritis of selected joints. Although there are extensive, uncontrolled experiences with DMSO that suggests its effectiveness in the treatment of musculoskeletal disorders, controlled trials yield conflicting results. The basis for the use of physical modalities such as phonophoresis and iontophoresis to improve topical drug efficacy is summarized.