Tobacco smoking causes cardiovascular, respiratory and malignant disease, and stopping smoking is among the key medical interventions to lower the worldwide burden of these disorders. However, the addictive properties of cigarette smoking, including nicotine inhalation, render most quit attempts unsuccessful. Recommended therapies, including combinations of counselling and medication, produce long-term continuous abstinence rates of no more than 30%. Thus, more effective treatment options are needed. An intriguing novel therapeutic concept is vaccination against nicotine. The basic principle of this approach is that, after entering the systemic circulation, a substantial proportion of nicotine can be bound by antibodies. Once bound to antibodies, nicotine is no longer able to cross the blood-brain barrier. As a consequence, the rewarding effects of nicotine are diminished, and relapse to smoking is less likely to occur. Animal studies indicate that antibodies profoundly change the pharmacokinetics of the drug and can interfere with nicotine self-administration and impact on the severity of withdrawal symptoms. To date, five phase I/II clinical trials using vaccines against nicotine have been published. Results have been disappointing in that an increase in quit rates was only observed in small groups of smokers displaying particularly high antibody titres. The failure of encouraging preclinical data to completely translate to clinical studies may be partially explained by shortcomings of animal models of addiction and an incomplete understanding of the complex physiological and behavioural processes contributing to tobacco addiction. This review summarizes the current status of research and suggests some directions for the future development of vaccines against nicotine. Ideally, these vaccines could one day become part of a multifaceted approach to treating tobacco addiction that includes counselling and pharmacotherapy.