Chronic pain, whether localized or generalized, is a widespread, often debilitating condition affecting > 25% of adults in the United States. Oral agents are the cornerstone of chronic pain treatment, but their use may be limited in certain patients, particularly the elderly. Topical therapies offer advantages over systemically administered medications, including the requirement of a lower total systemic daily dose for patients to achieve pain relief, site-specific drug delivery, and avoidance of first-pass metabolism, major drug interactions, infections, and systemic side effects. Several types of topical agents have been shown to be useful in the treatment of patients with chronic pain. Both capsaicin and topical diclofenac have been shown to be effective in the treatment of patients with chronic soft-tissue pain. In patients with hand and knee osteoarthritis (OA), the American College of Rheumatology generally recommends oral treatments (acetaminophen, oral nonsteroidal anti-inflammatory drugs [NSAIDs], tramadol, and intra-articular corticosteroids) and topical NSAIDs equally, favoring topical agents only for patients who have pre-existing gastrointestinal risk or are aged ≥ 75 years. Topical NSAIDs have been shown to provide relief superior to that of placebo and comparable to that of oral ibuprofen. Similarly, ketoprofen gel has been shown to be superior to placebo and similar to oral celecoxib in reducing pain in patients with knee OA. Different formulations of topical diclofenac (including the diclofenac hydroxyethyl pyrrolidine patch, diclofenac sodium gel, and diclofenac sodium topical solution 1.5% w/w with dimethyl sulfoxide USP) have been shown to be superior to placebo and comparable to oral diclofenac in the treatment of patients with pain due to knee OA, with a lower incidence of gastrointestinal complaints than with the oral formulation. In patients with neuropathic pain, topical forms of both capsaicin and lidocaine have been shown to be useful in the treatment of postherpetic neuralgia and diabetic peripheral neuropathic pain. Lidocaine has also demonstrated efficacy in relieving patient pain due to complex regional pain syndrome and may be useful in the treatment of patients with neuropathic pain who have cancer, although clinical trial results have not been consistent. Data suggest that topical therapies may offer a safe, well-tolerated, and effective alternative to systemic therapies in the treatment of patients with chronic, localized musculoskeletal and neuropathic pain.