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The menopausal transition is often marked by physical symptoms (e.g., vasomotor and sexual) and is sometimes accompanied by emotional changes that follow the decline in ovarian functioning. Although the absolute majority of women experience a smooth transition into postmenopausal years, this period in a woman's life has been associated, in some cases, with higher risk to develop depressive symptoms. Recent evidence supports the notion that the transition may also constitute a “window of vulnerability” for some women to develop new-onset or recurrent depression. Serotonergic and noradrenergic antidepressants as well as transdermal estradiol have been shown to be effective in alleviating depressive and vasomotor symptoms in symptomatic, midlife women. In this review, the authors discuss the epidemiology of depression during the menopausal transition and update the current biological treatment strategies used to manage this condition in midlife women.