In pain processing and modulation, serotonin (5-hydroxtryptamine, 5-HT) has excitatory (hyperalgesic) and inhibitory (analgesic) actions, depending on the site of action, the cell type and the type of receptor. In the periphery, 5-HT sensitizes afferent nerve fibers, thus contributing to inflammatory and neuropathic hyperalgesia. In the trigeminal system, agonism at 5-HT1B/D receptors reduces neurotransmitter release, whereas actions through the 5-HT2A receptor may underlie chronic headache. Genetic alterations in the 5-HT system may influence the susceptibility to migraine and to other pain disorders. 5-HT is involved in descending inhibitory pathways in the CNS, and modulation of this system is the most likely mechanism of action of antidepressant drugs in analgesia. Recently, facilitatory serotonergic pathways have been discovered, which may be functionally important.