The brain is highly susceptible to focal or global ischemia. Unless ischemia is promptly reversed, reperfusion produces further cerebral damage. Acute thrombolysis or defibrinogenation is effective only in selective patients with ischemic stroke and carries a significant risk of bleeding complications. Whereas numerous neuroprotectants were shown to be effective in experimental studies, none of them have been shown to work in clinical trials. The major pathogenetic mechanisms of ischemia/reperfusion injury include excitotoxicity, disturbed calcium ion homeostasis, overproduction of nitric oxide and other free radicals, inflammation, and apoptosis. Nitric oxide and other free radicals, the key mediators of excitotoxicity and disturbed calcium ion homeostasis, cause direct injury and also indirectly damage via inflammation and apoptosis. Melatonin is a potent free radical scavenger and an indirect antioxidant. This mini review summarizes the in vivo and in vitro evidence that melatonin protects against ischemia/reperfusion injury. There is convincing evidence from the literature that melatonin treatment is highly effective in different in vivo and in vitro models of excitotoxicity or ischemia/reperfusion in multiple animal species. Melatonin is safe and non-toxic in humans, and its administration via the oral route or intravenous injection is convenient. While more experimental studies should be conducted to further explore the neuroprotective mechanisms and to document any synergistic or additive protection from combining melatonin with thrombolysis, defibrinogenation or other neuroprotectants, interested clinical scientists should consider planning phase II and III studies to confirm the benefit of melatonin as an acute stroke treatment or a preventive measure for stroke patients.