The focus of this chapter is the relationship between the onset of depression in women and the reproductive events of the perimenopause. The perimenopause is a time of considerable variability in reproductive function, which appears in some women to be associated with an increased susceptibility to depression. Elevated gonadotropin levels occur during the late perimenopause, with plasma follicle-stimulating hormone levels increasing in association with impaired ovarian function and decreased estradiol secretion. It is unclear, however, whether the variability in ovarian hormone secretion during the perimenopause has a substantial causal role in the development of depression. Epidemiologic studies have documented that most women do not become depressed during the menopausal transition. However, recent longitudinal studies suggest that in some women, perimenopause-related reproductive events play a role in the onset of depression. Additionally, randomized controlled trials have documented the short-term (3-6 weeks) antidepressant efficacy of estradiol in depressed perimenopausal women. Thus, although depression is not a uniform accompaniment of the menopausal transition, in some women age-related changes in ovarian estrogen production may alter central nervous system function and predispose them to develop depression.