The role of estrogen in the treatment of depression is reviewed. The relation is examined in studies of perimenopausal and postmenopausal women with depressed mood, in studies of depressive disorders, and in studies of estrogen as an adjunct to antidepressant medication. The literature has many methodologic shortcomings, including combining women of various ages, failure to confirm life stage, the use of different types of estrogens, the inclusion of women with a range of mood disturbances, and the enrollment of women with concurrent psychiatric illness. There are few controlled evaluations of the use of estrogen to supplement ongoing antidepressant treatment. Estrogen alone seems to be beneficial for improving mood in perimenopausal and postmenopausal women. Estrogen is superior to placebo for reproductive-related mood disorders, including postpartum depression and mild depressive disorders during perimenopause. Replication is necessary, especially in moderate to severe levels of major depression. Estrogen may augment antidepressant treatment. Assessment and treatment implications are discussed.