In contrast to current pharmacotherapies, immunologic approaches to treating tobacco dependence target the drug itself rather than the brain. This approach involves the use of nicotine-specific antibodies that bind nicotine in serum, resulting in a decrease in nicotine distribution to the brain and an increase in nicotine's elimination half-life. This review summarizes the literature examining the effects of immunologic interventions on the pharmacokinetics and behavioral effects of nicotine in animal models, as well as recent phase I and II clinical trials in humans. Studies using various vaccines and nicotine-specific antibodies in rodents have shown that immunization can significantly reduce the behavioral effects of nicotine that are relevant to tobacco dependence (eg, nicotine self-administration). These findings provide proof of principle that immunologic interventions could have utility in the treatment of tobacco dependence. Thus far, phase I clinical trials of nicotine vaccines have not produced any serious adverse events in humans and have produced dose-dependent increases in serum antibody levels. Although preliminary data from these small trials suggest that vaccination can facilitate abstinence from tobacco use, more advance trials are needed. By acting outside the nervous system, immunologic approaches are less likely to produce the adverse side effects associated with current medications. In addition, the unique mechanism of action of immunotherapy makes it particularly suitable for combination with other pharmacological approaches. Taken together, the work completed to date provides substantial evidence that immunologic interventions could play an important role in future treatment strategies for tobacco dependence.