Epidemiologic and clinic data have unequivocally supported the notion that women experience more psychiatric problems at some point in their lives compared with men, particularly mood and anxiety symptoms and sleep problems. It is also known that, for some women, such increased risk might be associated with reproductive cycle events such as the postpartum period or the menopausal transition. These periods are not only marked by substantial hormone variations but also quite often accompanied by stressful events and changes in personal, family and professional responsibilities. The complexity of these reproductive-related ‘windows of vulnerability’ poses a challenge to physicians and other professionals dedicated to women's health across the lifespan. The menopausal transition and early postmenopausal years constitute a characteristic example; during this period in life, dynamic changes in sex hormones and reproductive function cooccur with modifications in metabolism, sexuality, lifestyle behaviours and overall health, sometimes affecting a woman's quality of life and overall functioning. For most women, however, this transition has little or no significant impact on their mental wellness. A prior depressive episode—particularly if related to reproductive events—is the strongest predictor of mood symptoms or depression during menopausal years. Also, the presence and severity of vasomotor symptoms and other health-related issues appear to modulate the risk for depression in midlife women. Mechanistically, estrogen plays an important modulatory role in mood and cognitive regulation, hence the effects noted when midlife women are exposed to significant estrogen fluctuations or to estrogen-based therapies (use or withdrawal). Transdermal estradiol, as well as serotonergic and noradrenergic antidepressants, have shown efficacy in the management of depression in this population. Other evidence-based treatment options (hormonal, pharmacological, behavioural) are available to clinicians and health professionals who care for this population.