There are nearly 1.1 billion users of nicotine and tobacco products worldwide. Tobacco use through cigarette smoking is the leading preventable cause of death in the world and kills nearly four million people annually. However, although some cigarette smokers are able to quit, many are not, and standard medications to assist in smoking cessation (e.g. nicotine-replacement therapies and sustained-release bupropion) are ineffective in many remaining smokers. Recent developments in our understanding of the neurobiology of nicotine dependence have identified several neurotransmitter systems that might contribute to the process of smoking maintenance and relapse, including dopamine, noradrenaline, 5-hydroxytryptamine, acetylcholine, endogenous opioids, GABA, glutamate and endocannabinoids. Several existing medications are being tested as treatments for nicotine dependence and novel investigational agents are under development as effective treatments for nicotine dependence in the 'hard to treat' tobacco user.