A link between smoking and depressive symptoms has been described in the literature for over a decade. The neurotransmitter systems affected by cigarette smoke mirror the neurotransmitter pathways thought to be involved in the biological mechanisms of depression. Cigarette smoke contains several psychoactive chemicals; nicotine is the best studied among these and is widely accepted to be the addictive substance in tobacco. Nicotine binds to nicotinic receptors in the brain, augmenting the release of numerous neurotransmitters, including dopamine, serotonin, norepinephrine, acetylcholine, gamma-aminobutyric acid, and glutamate. Cigarette smoke has other psychoactive properties apart from nicotinic receptor stimulation. For example, it inhibits monoamine oxidase (the enzyme responsible for breaking down the biogenic amine neurotransmitters norepinephrine, serotonin, and dopamine) in the brain. Various antidepressants act through modulation of the biogenic amine neurotransmitter pathways. That the neural substrates modified by both smoking and antidepressant drugs overlap has relevance to smoking cessation. The use of antidepressants as adjuvants to smoking-cessation treatment can enhance cessation success rates. Understanding the neurobiological mechanisms underlying the association between smoking and depression may improve physicians' ability to assist smokers in their efforts to quit and will contribute to a more thorough comprehension of both the biology of addiction and the etiology of depression.