This review considers some of the novel therapies that are under development for the treatment of tobacco dependence, outlines their efficacy in clinical studies and explains their mechanisms of action in terms of contemporary theories for the psychobiology of the dependence. It focuses on three treatments with differing mechanisms of action that are at different stages of clinical development. The first is varenicline, a partial agonist at the alpha4beta2 nicotinic receptors, which are thought to play a central role in the addiction to nicotine. Preclinically, this drug mimics the effects of nicotine on dopamine (DA) release in the nucleus accumbens when given alone but attenuates this response to a subsequent nicotine challenge and reduces nicotine self administration. Very encouraging results have been seen in the five clinical studies that have been reported with this drug. The second compound, rimonabant, is a cannabinoid CB1 receptor antagonist. Preclinically, this compound reduces nicotine self administration, DA turnover in nucleus accumbens and attenuates reinstatement of nicotine-seeking behaviour. Clinically, the drug is well tolerated but its effects on smoking cessation are equivocal. However, it has the valuable additional property of inhibiting post-cessation weight gain. Nicotine 'vaccines' are the final group of treatments considered, which involves raising antibodies in the blood that limit the amount of nicotine that penetrates into the brain, thereby reducing the psychopharmacological responses to the drug. The vaccines also reduce DA turnover in nucleus accumbens and reinstatement of nicotine-seeking behaviour after nicotine readministration. The three vaccines discussed are well tolerated and show signs of good efficacy; however, the increase in antibody titre, evoked by the treatment, shows significant inter-individual variation and is generally short lived. Thus, although this approach may provide a valuable aid to smoking cessation, it seems unlikely that it can be used for primary prevention.