Many patients with depression fail to derive sufficient benefit from available treatment options, with up to a third never reaching remission despite multiple trials of appropriate treatment. Novel antidepressant agents are needed, and drugs targeting nicotinic acetylcholine receptors (nAChRs) appear to hold promise in this regard. nAChRs are involved in a variety of neurobiological systems implicated in the pathophysiology of depression. In addition to their role in cholinergic neurotransmission, they modulate dopamine function and influence inflammation and hypothalamic-pituitary-adrenal axis activity. Preclinical studies have suggested antidepressant-like effects of drugs targeting nAChRs, with the most consistent results observed with alpha4beta2 nAChR modulators such as varenicline and nonspecific nAChR antagonists such as mecamylamine. These agents appear to offer the most potential antidepressant-like efficacy when used in conjunction with other established antidepressant treatments. nAChR modulators also influence neural processes that appear to mediate the behavioral effects of antidepressants, such as hippocampal cell proliferation. Clinical evidence, while limited, shows preliminary efficacy for mecamylamine and varenicline. Taken together, the preclinical and clinical evidence suggests that drugs targeting nAChRs may represent an important new approach to the treatment of depression.