Serotonin (5-hydroxtryptamine, 5-HT) is an important molecule in pain processing and modulation. Whether 5-HT has an analgesic or hyperalgesic action depends on the cell type and type of receptor it acts on. In the periphery, 5-HT sensitizes afferent nerve fibers, thus contributing to hyperalgesia in inflammation and nerve injury. In the trigeminal system, agonism at 5-HT1B/D receptors reduces neurotransmitter release, but actions through the 5-HT2A receptor may underlie chronic headache. Furthermore, genetic alterations in the 5-HT system may influence the susceptibility to migraine. In the central nervous system, 5-HT is involved in descending inhibition, but facilitatory serotonergic pathways may be functionally more important.