Recent studies have suggested that serotonergic neurons exert a phasic, rather than a tonic, influence on integrated functional activity in the central nervous system. 43,44. Thus 5HT neurons in the raphe nuclei are characterized by a slow spontaneous rate of firing, usually below 2.5 Hz1,2 and this quiescent state typically observed in awake animals dicreases to near zero during sleep 113. The fact that 5 HT innervate almost all regions of the central nervous system indicates that this indoleamine plays an important role in the phasic modulation of most systems of the brain. The present chapter has focused on the organization of ascending 5HT pathways that may be involved in pain modulation. It is clear that 5HT pathways affect pain transmission nuclei but most of the studies to date have focused on modulation of nociception by descending 5HT projections to the spinal cord dorsal horn. Above the evidence supporting ascending 5HT modulation of nociception at the level of the reticular formation, thalamus and somatosensory cortex has been reviewed. In addition the concept of possible 5HT modulation of components of the endogenous pain suppression system is presented. Although this discussion was limited to possible 5HT modulation of neurons in the nucleus raphe magnus, periaqueductal gray, locus coeruleus and substantia nigra, it is likely that several other nuclei postulated to be involved in the descending pain modulatory system are influenced by 5HT as well. Further physiological, pharmacological and behavior work is clearly necessary to delinate the relative importance of ascending 5HT modulation of neurons in the pain transmission and pain suppression pathways and to determine the relative effect of such modulation on the antinociception experienced by the animal.