Smoking cessation has major health benefits for men and women of all ages. However, most smokers are addicted to nicotine and fail repeatedly in their attempts to quit. Stimulation of nicotinic receptors in the brain, particularly alpha4beta2 receptors, releases dopamine in the meso-limbic area of the brain and is reinforcing. Nicotine abstinence reduces dopamine release, and this is associated with withdrawal symptoms and craving for nicotine. Eight current pharmacotherapies--bupropion, nortriptyline, clonidine and nicotine patch, gum, inhaler, lozenge and nasal spray--are moderately effective aids to smoking cessation. Each is significantly better than placebo, but approximately 80% of patients using one of these medications return to smoking within the first year. Varenicline, a specific alpha4beta2 nicotinic receptor partial agonist, is a new pharmacotherapy that stimulates dopamine and simultaneously blocks nicotine receptors. Phase II and III trials have yielded promising results suggesting that varenicline could be an important advance in the treatment of nicotine dependence.