Most evidence in the literature concerning the role of serotonin in ischemia originates from brain research. This is partly because the central nervous system is particularly prone to accumulation of 5-HT, due to the neuronal sources of the amine in addition to circulating 5-HT from platelets. In ischemia, platelet invasion, rupture of the blood-brain barrier, liberation of 5-HT from nerve terminals inside the vessel wall, and necrosis of serotonergic neurons favor local increases of the transmitter in the brain. The pathophysiological consequences include amplifications of processes such as vasoconstriction of major and collateral arteries, edema formation, platelet aggregation, and blood sludging. 5-HT2 receptors appear to be the major effector of these actions of serotonin, judging from experimental and clinical pharmacology data with specific or partial 5-HT2 serotonergic antagonists. This review summarizes current knowledge on the key role serotonin plays in the induction or consequences of brain ischemia.