Depression, with or without concomitant anxiety, is one of the most burdensome medical conditions worldwide. Depression affects women more often than men and may cause significant impairment. Reproductive phase-related windows of vulnerability for depression (new or recurrent) have been recognized, including the menopause transition. Midlife depression is likely influenced by both menopause- and nonmenopause-related factors. Antidepressants and cognitive behavioral therapy remain first-line treatment options for moderate to severe major depressive disorder at any time, with proven efficacy and tolerability in midlife women. Transdermal estradiol can also be part of the treatment armamentarium, but its use as a prophylaxis against midlife depressive symptoms, although promising, warrants further investigation.