Current evidence suggests that pharmacotherapy may result in further improvements in smoking cessation, doubling or tripling quit rates achieved by nonpharmacological means. Professor Stephen I. Rennard and Dr. Michael A. Chandler, Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA, review the pharmacological basis for smoking cessation, with special emphasis on first-line treatments. Regarding nicotine replacement therapy (NRT), the most widely used pharmacotherapy for the treatment of tobacco dependence, all forms of administration (gum, lozenge, patch, nasal spray or inhaler) appear equally efficacious, although the authors point out that heavy smokers may benefit from higher doses. After describing the major points of each form of NRT administration, Professor Rennard and Dr. Chandler express their opinions about an important concern for both physicians and patients: NRT safety. In this vein, the authors summarize the evidence provided by the most recent clinical studies on this topic. Forms of nonnicotine pharmacotherapy, including bupropion, other antidepressants, clonidine, varenicline, and combination therapy (supplementing transdermal nicotine with short-acting NRT products) are described in great detail, including action mechanisms, dosage, and side effects. Concerning varenicline, a recent study that compared varenicline to NRT as an active comparator is reviewed, emphasizing that significant reduction in nicotine craving, withdrawal symptoms, and smoking satisfaction were detected with varenicline use. Additionally, the authors discuss the cost-effectiveness of smoking cessation pharmacotherapy, in order to encourage practitioners not to reserve pharmacotherapy for refractory cases. In conclusion, future directions are described, including clinical trials involving cannabinoids and receptor antagonists as well as further animal studies.