Despite significant reductions over the past 45 years in the percentage of individuals smoking cigarettes, tobacco-related illnesses remain the leading cause of preventable death in the United States. Although the health risks of tobacco use have been clearly outlined, addiction to nicotine traditionally has been one of the more challenging habits to break. Seven first-line therapies to treat tobacco use and dependence are available; however, annual quit rates remain surprisingly low, suggesting that continued research and development in the area of smoking cessation are warranted. In an attempt to improve long-term quit rates and blunt the reinforcing effects of nicotine in the brain, the nicotine conjugate vaccine was developed as a novel approach for the treatment of nicotine dependence. Vaccine administration produces nicotine-specific antibodies that bind to nicotine from exogenous sources, creating a large unit that is not able to cross the blood-brain barrier, which limits the rate and extent of nicotine absorption into the brain. Results of clinical trials indicate that individuals achieving high nicotine-specific antibody levels with the nicotine conjugate vaccine have greater success with smoking cessation at 12 months compared with those with lower levels. Adverse effects associated with the nicotine conjugate vaccine have been primarily mild and localized in nature, with minimal systemic effects. The most commonly reported adverse effects include tenderness and ache at the injection site, general discomfort, headache, and muscle ache. Awaiting results of phase III trials, the true clinical utility of the nicotine conjugate vaccine is yet to be realized, although this investigational vaccine represents a distinctive administration model that may improve patient adherence and increase the ability to achieve abstinence from cigarette smoking.