The search for effective drugs that will curtail neural damage resulting from transitory interruption of the blood supply to the brain has a long investigative history. Unfortunately, many chemical agents that were shown to be effective in reducing brain ischemia/reperfusion (I/R) injury in animals have been found to be much less beneficial or totally ineffective in humans. In the last 15 years, melatonin has been widely tested in terms of its ability to reduce the morphological damage, biochemical and molecular alterations and behavioral disturbances resulting from I/R injury in animals, usually rodents. These studies have documented that melatonin is highly beneficial in terms of reducing the changes that accompany transitory ischemia of the brain followed by reperfusion with oxygenated blood. Melatonin’s protective actions are attributed to its potent direct free radical scavenging activity, its stimulation of antioxidative enzymes, its ability to suppress the inflammatory response, and its actions in preserving cellular homeostasis and preventing molecular events that culminate in apoptosis, etc. In view of its uncommonly low toxicity and high efficacy, it seems appropriate to give melatonin consideration for use in the human with the intent of reducing the numerous negative aspects of stroke.