Cluster headache is a highly disabling primary headache disorder, characterized by unilateral headache attacks occurring in association with cranial autonomic symptoms. Serotonergic agents, such as the ergot alkaloids, have traditionally been used for the acute and preventive treatment of cluster headache and other primary headaches. Although it initially was thought that their efficacy was due solely to the vasoconstriction of extracranial cerebral vessels, new mechanisms of action of these drugs have been ascertained as a consequence of advances in elucidation of the pathogenesis of primary headaches and the development of triptans. This article reviews the current knowledge about serotonergic agonists and antagonists used in the management of cluster headache, focusing on their mechanisms of action and on the possible role of serotonin system dysfunction in this complex disorder.