Nicotine dependence is still the major preventable cause of death in the developed world, and has strong comorbity with mood disorders including major depression. Depressed patients are more likely to smoke cigarettes, and quitting can precipitate an episode of depression in some subjects. Interestingly, antidepressants, particularly the atypical antidepressant buproprion, are therapeutics that can help smokers quit. Despite these observations, the underlying biological factors of the relationship between smoking and depression remain unclear. Results from clinical and pre-clinical studies have seemed somewhat paradoxical because heightened cholinergic activity can induce depression while both nicotine and nicotinic antagonists can be antidepressant-like. These observations can be reconciled by considering that high affinity nicotinic receptors in the brain can be desensitized by chronic nicotine use, leading to blunted cholinergic activity. Based on this hypothesis, nicotinic antagonists have recently been tested as treatments for depression in human subjects, particularly as adjunct therapy along with classical antidepressants. These data suggest that the relationship between smoking and depression may be partially explained by the fact that depressed patients smoke in an effort to self-medicate depressive symptoms by desensitizing their nicotinic receptors. This possibility suggests new avenues for treatment of both nicotine dependence and depressive disorders.