Abstract: Despite the well-known adverse health effects of tobacco smoking, numerous studies have shown that nicotine, the principal pharmacologically active alkaloid in tobacco smoke, exerts neuroprotective properties in several animal models of neurodegeneration. Furthermore, cigarette smoking appears to significantly reduce the risk of developing Parkinson's disease in human subjects. We review the animal and human studies that investigated possible neuroprotective actions of nicotine and other nicotinic receptor agonists and antagonists. We demonstrate that nicotine is not neuroprotective in all animal models of neurodegenerative disease. In fact, C57Bl/6 mice pretreated with nicotine have an increased sensitivity to 3-nitropropionic acid, a neurotoxin used in mice to mimic some aspects of Huntington's disease. The actions of nicotine on dopamine release may explain the variable effects of nicotine in animal models of Parkinson's and Huntington's diseases. Finally, we focus on some future directions for studies that evaluate neuroprotective properties of nicotinic agonists and antagonists.