The neurobiological substrate of nicotine dependence has been the subject of extensive preclinical and clinical research. Many experimental reports have implicated the brain serotonin (5-HT) systems in processes relevant to nicotine dependence, but the specific role of this neurotransmitter system largely remains to be elucidated. This review will focus on the role of 5-HT in the acute and chronic effects of nicotine. In particular, the evidence for a role of 5-HT neurotransmission in brain processes thought to be involved in positive and negative control of nicotine use will be examined, and potential clinical implications discussed.