Perimenopause, the interval of irregular menstrual activity which directly precedes menopause, is characterized by widely fluctuating hormone levels amidst a large-scale decline in circulating estrogen. This phase in a woman's life is typically accompanied by physical discomforts including vasomotor symptoms, such as headaches, insomnia, and hot flushes, as well as genital atrophy. Not surprisingly, studies suggest a significant increase in mood lability for women during this time. While some evidence points toward an exacerbation of bipolar mood symptoms and an increase in schizophrenic psychosis during perimenopause, the majority of research conducted on perimenopausal mental disorders has focused on unipolar depression. Studies vary widely in methodology, definitions of menopausal status, and degrees of depression among subjects; however, the majority of findings indicate an increased susceptibility to depression during the perimenopausal transition. This greater susceptibility may be due to neuroendocrine effects of declining estrogen levels, the subjective experience of somatic symptoms resulting from this hormonal decline, and/or the more frequent occurrence of “exit” or “loss” events for women during this stage of life. At this time, more research is needed to address questions of prevalence, risk, and etiology for depression and other major mental disorders as related to the physiological and psychosocial changes associated with perimenopause.