Traditionally, opioids exert analgesic effects through actions within the central nervous system (CNS) exclusively (1). Recently, however, evidence has begun to accumulate that opioid antinociception can be initiated by activation of opioid receptors located outside the CNS. One of the earliest reports was that of Wood (2) who found that morphine elicited analgesic effects when applied topically to “painful areas” in the periphery. Numerous clinical and experimental reports of similar observations have occurred since. However, most of the former are merely anecdotal, and many of the latter were discounted because they did not demonstrate principal criteria for opioid receptor-mediated effects, in particular naloxone reversibility. Moreover, the question as to whether these effects result from a truly peripheral rather than from a central site of action (e.g., via uptake of the drug into the circulation and transport to the CNS) has been discussed repeatedly. This paper will give an overview of controlled experimental and clinical studies examining peripheral antinociceptive actions of opioids and will discuss mechanisms and potential implications for novel therapeutic approaches.