The relationship between smoking and depression is bidirectional. Recent research has focused on nicotine's neurobiologic impact on the brain as it relates to depression. Genetic factors are also important and may account for up to 67% of smoking initiation, maintenance, and dependence. Because nicotine withdrawal may mimic and induce depression, appropriate clinical evaluation and treatment are essential to reduce the high morbidity and mortality associated with smoking and depression and maximize smoking cessation rates.