Tobacco smoking in humans is one of the most persistent and widespread addictions and is driven by nicotine in tobacco smoke. Over the last several decades, understanding of the molecular and cellular basis for nicotine addiction has increased tremendously as a result of pharmacological, molecular genetic, electrophysiological and behavioral studies of nicotine reinforcement. Studies of the biological basis for nicotine reinforcement has helped in the design of new treatments for smoking cessation such as varenicline; however, smokers report that they smoke for many reasons, including the ability to control symptoms of anxiety and depression or the desire to control appetite. Further, developmental exposure to tobacco smoke increases the likelihood of adult smoking. Here we review what is known about the molecular and circuit basis for a number of behaviors related to tobacco smoking. Leveraging the knowledge from studies of different behaviors mediated by nicotine receptors in multiple brain circuits could provide points of convergence that will inform future therapeutic development for smoking cessation. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.