There is little doubt that women experience a heightened psychiatric morbidity compared to men. A growing body of evidence suggests that, for some women, the menopausal transition and early postmenopausal years may represent a period of vulnerability associated with an increased risk of experiencing symptoms of depression, or for the development of an episode of major depressive disorder. Recent research has begun to shed some light on potential mechanisms that influence this vulnerability. At the same time, a number of studies and clinical trials conducted over the past decade have provided important data regarding efficacy and safety of preventative measures and treatment strategies for midlife women; some of these studies have caused a shift in the current thinking of how menopausal symptoms should be appropriately managed.Essentially, most women will progress from premenopausal into postmenopausal years without developing significant depressive symptoms. However, those with prior history of depression may face a re-emergence of depression during this transition while others may experience a first episode of depression in their lives. Here I provide an overview of what is known about risk factors for depression and the risk posed by the menopausal transition, its associated symptoms, and the underlying changes in the reproductive hormonal milieu, discussing the evidence for the occurrence of mood symptoms in midlife women and the challenges that face clinicians and health professionals who care for this population.