Nicotine is the crucial component in tobacco that underlies smoking behavior; however, the effects of nicotine can vary in both human and animal studies. Recent data from knockout mouse studies, neurotransmitter release studies and electrophysiological experiments support the hypothesis that conflicting behavioral effects elicited by nicotine can result from the activation of different subtypes of nicotinic acetylcholine receptors and the stimulation of antagonistic neuronal pathways. Thus, small differences in the activation state, connectivity or sensitivity of neuronal pathways among individuals might result in large differences in behavioral responses to nicotine. An understanding of the molecular and cellular processes that oppose nicotine reinforcement will be crucial for the development of new interventions to initiate smoking cessation or to prevent the transition from occasional smoking to dependence.