The identification of opioid systems led to much of the early work on pain pharmacology being based on understanding inhibitory mechanisms of analgesia. However, hyperalgesia and allodynia are common clinical symptoms and therefore hyperexcitability must be a major component of pain. Thus, the emphasis of current research into pain has shifted to understanding excitatory pathways that underlie neuronal sensitization and potentiation. Although much evidence supports the presence of descending inhibitory mechanisms of pain, reports of facilitatory pathways from the brainstem have been scarce. In this article, we review evidence for facilitatory 5-HT pathways that link spinal cord and brainstem areas involved in mood and emotions. Because pain encompasses affective aspects, we suggest that these 5-HT pathways and other circuits are important in determining the levels of pain, the outcome of drug treatments and provide a mechanism whereby emotions can alter pain perception.