Data regarding the increased incidence of psychiatric illness during midlife in women are still conflicting. However, there is a growing consensus that certain groups of women may in fact be at higher risk for mood symptoms and psychiatric disorders during the perimenopausal transition. Mood symptoms during the perimenopause may be related to mood disorders during other periods of hormonal fluctuation throughout a woman's reproductive lifecycle. Elucidating these associations may advance the understanding of mood disorders during the perimenopausal transition. The epidemiology and treatment of perimenopausal mood symptoms compared with the epidemiology and treatment of mood disorders during the late luteal phase of the menstrual cycle, pregnancy, and postpartum. Common risk factors associated with mood disorders during these periods of hormonal changes or instability include poor lifestyle habits, a history of hormonally related mood disorders, stress and negative life events, ethnicity, and comorbidity. Reproductive-related mood disorders also are subject to an improvement in symptoms in response to treatment with selective serotonin reuptake inhibitors. As the morbidity associated with mood disorders during midlife may be quite significant, and as life expectancy continues to increase, recognition, prevention, and treatment of perimenopausal affective illness is becoming increasingly essential.