Objective: This review tries to consolidate the literature on changes in serotonin and the importance of these changes for understanding headache pathogenesis and determining treatment. A model is presented that integrates previous serotonin studies and offers an explanation for apparent contradictions in the literature.Data Sources: Fifty-four journal articles that described a relationship between serotonin and headache in animal and human models were identified through Medline search and bibliography and reviewed. Alterations in serotonin, headache, and clinical situations influencing headache activity were examined.Data Synthesis: Abnormalities in blood vessels have traditionally been implicated in the pathogenesis of migraine headaches, and excessive muscle contraction in tension-type headaches. Interestingly, both vascular and muscular changes occur in both migraine and tension-type headache. Recently, biochemical changes have been demonstrated in both types of headaches. These biochemical changes are postulated to precede and possibly cause the subsequent changes in blood vessels and muscle tone, known to occur in chronic headaches. Serotonin has been the most widely studied neurochemical in relation to headaches. Apparently contradictory results have been shown, such as increasing serotonin levels both increasing and decreasing headaches.Conclusions: Serotonin plays an important role in the pathogenesis of headaches. Changes in serotonin may precede the vascular and muscular changes of migraine and tension-type headaches. The influence of serotonin on headaches explains a number of clinical situations that affect headache activity and the variety of classes of effective headache medications.