Tobacco dependence is a chronic disease that often requires repeated interventions and multiple attempts to quit. To date, three medications are FDA-approved for smoking cessation: nicotine replacement therapy, sustained-release bupropion, and varenicline. These treatments are effective across a broad range of populations, and are recommended for all smokers, including those with psychiatric or addictive comorbidity. Less is known however concerning the benefit-risk profile of these medications in pregnant women and adolescents. With these limitations in mind, clinicians should encourage and offer counseling and a prescription of pharmacotherapy to every patient willing to make a quit attempt. Despite the relative efficacy of first-line medications, many smokers relapse after one given quit attempt, and alternative pharmacotherapies are needed. Clonidine and nortriptyline have been proposed as second-line medications. In addition, this review indentifies a series of promising drugs that hopefully will be available to complete our current armory.