Nicotine in tobacco is the primary reason why most people find it hard to stop using tobacco. Nicotine creates dependence by activating the dopaminergic reward system in the brain. Physiologic withdrawal symptoms that occur when nicotine is no longer administered reinforce continued nicotine administration to avoid withdrawal. Extrapolating from this evidence has led to the development of tobacco dependence pharmacotherapy based upon the concept of replacing and/or blocking the effects of nicotine in the brain. The efficacy of nicotine replacement and blockade treatments in lessening symptoms of nicotine withdrawal and increasing quit rates has been consistently demonstrated in clinical trials. Despite the availability of efficacious medications to treat nicotine dependence, current therapies remain underutilized across the population. Health-care providers need to systematically encourage all tobacco users to quit and ensure that their tobacco-using patients use evidence-based treatments when they attempt to quit.