There has been a huge and exciting increase in our recent understanding of the pathogenesis of pain. Neurophysiological and pharmacological evidence have demonstrated that 5-HT now plays an important albeit discrete role in pain transmission at various levels of the pain pathway. Although 5-HT is clearly involved in spinal analgesia, its mode of action is still obscure and perplexing perhaps because it has multiple and often opposing effects mediated by its multiple receptor subtypes. The involvement of 5-HT3 antagonists and agonists have been found to either facilitate or inhibit nociceptive processing in the dorsal horn cells. Thus the understanding of the descending serotonergic analgesic system may enable the development of new non-opioid, non-addictive analgesics.