Tobacco use is strongly driven by the pharmacological actions of nicotine in the central nervous system. This review will summarize some of the seminal research findings relating to nicotine dependence and will highlight fundamental questions that must yet be answered. The evidence that nicotine is an addictive drug was summarized in the 1988 Report of the Surgeon General which concluded that nicotine fulfills the criteria for a dependence-producing drug. More recently, research has further characterized the pharmacological effects of nicotine in the brain and elucidated the basic pathophysiology of nicotine addition. Moreover, research shows that nicotine replacement therapy, such as nicotine patch or gum, can prevent or reverse withdrawal symptoms. It is also clear that the form of nicotine delivery is a major determinant of addiction potential and that cigarettes and smokeless tobacco products are both highly engineered drug delivery devices that act not only to provide users with controllable doses of nicotine, but also to maximize the addictive effects of nicotine. Along with the understanding of the dependence process has come a rapidly expanding arsenal of treatment for the disorder. There are many major questions about the nature and course of nicotine addiction that remain unanswered and must be addressed if we are to continue to improve our ability to prevent tobacco dependence as well as to provide more effective and acceptable options for treatment and disease prevention in those who are already addicted.