Neurodegenerative diseases are chronic and progressive disorders characterized by selective destruction of neurons in motor, sensory and cognitive systems. Despite their different origin, free radicals accumulation and consequent tissue damage are importantly concerned for the majority of them. In recent years, research on melatonin revealed a potent activity of this hormone against oxidative and nitrosative stress-induced damage within the nervous system. Indeed, melatonin turned out to be more effective than other naturally occurring antioxidants, suggesting its beneficial effects in a number of diseases where oxygen radical-mediated tissue damage is involved. With specific reference to the brain, the considerable amount of evidence accumulated from studies on various neurodegeneration models and recent clinical reports support the use of melatonin for the preventive treatment of major neurodegenerative disorders. This review summarizes the literature on the protective effects of melatonin on Alzheimer disease, Parkinson disease, Huntington's disease and Amyotrophic Lateral Sclerosis. Additional studies are required to test the clinical efficacy of melatonin supplementation in such disorders, and to identify the specific therapeutic concentrations needed.