Due to partial efficacy and adverse-event burdens, limited success has been achieved in the treatment of many chronic pain conditions with traditional, systemically administered analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, opioids, antidepressants, and anticonvulsants. Additionally, it is not uncommon for patients suffering from chronic pain to have complex medication regimens to treat their pain and other medical conditions and yet still experience both their pain and bothersome medication adverse events. An alternative to systemic analgesics for the treatment of chronic pain is the use of analgesics applied directly to the site of pain on the skin, ie, topically, that possess a peripheral mechanism of action. Apparent clinical advantages of topical drug delivery include significant reduction of systemic adverse events secondary to extremely low systemic exposure to medication, minimized risk of drug interactions, and elimination of what can often be a lengthy dose titration period. Over the past decade, further knowledge of the anatomy and neurochemistry of peripheral nociceptors has identified a number of viable targets for topically applied analgesics (topiceuticals). Moreover, studies in both inflammatory nociceptor and neuropathic pain models have clearly demonstrated pain behaviors can be significantly reduced by blocking or dampening pain generation in the periphery. We provide here some background on the physiology and pathophysiology of peripheral nociceptive afferents and the mechanisms of action of various topical analgesics. Over the past decade, there has been a significant increase in the use of topiceutical analgesic drugs worldwide and a growing body of evidence for their efficacy, safety, and tolerability. A review of the clinical data on the treatment of chronic pain with topical analgesics is also presented.