Several pharmacological, neurophysiological and immunohistological studies indicate that exogenous or endogenous opioids can have antinociceptive effects by acting at peripheral sites. Although modulation of mu, delta and kappa receptors can mediate these effects, the nature of the noxious stimulus and the underlying pathological condition may affect the types of opioid receptors involved. Thus, it would be appropriate to develop peripherally-acting opioid analgesics that do not have the untoward central side effects often associated with conventional analgesic drugs. This paper reviews the evidence supportive of a peripheral mechanism of action for opioids.