Throughout their childbearing years, women are twice as likely as men to experience an episode of major depression. The exact etiology of this difference is unclear, but psychosocial and neurobiologic factors likely contribute. Clinicians should consider gender differences in the phenomenology of depression and response to antidepressant treatment when screening for depressive illness, selecting appropriate treatment and assessing therapeutic response. Treatment considerations when selecting an antidepressant should include the patient's gender, age, and, in women, menopausal status, including the use of concomitant HRT. Further research is needed to refine and extend the existing knowledge base regarding the effect of gender on treatment of depression, including the role of endogenous and exogenous gonadal hormones in response to antidepressant treatment.