Beyond the repeatedly confirmed finding that women diagnosed with mood disorders greatly outnumber men lies a widely varying set of hypotheses that attempt to explain the suspected causes, incidence, symptoms, and comorbidities from various perspectives. Several complex factors, however, have impeded attempts to study why women are so vulnerable to depression. This article examines the problems associated with studying affective disorders in women and reviews the current hypothetical constructs of the etiology and pathophysiology of depression and their potential relevance to the disproportionate number of women with unipolar depression. The association of depression to biological stages of a woman's life and the differences between the biology of men and women are described, and the potential social, psychological, and environmental factors that might particularly promote the development of depression in women are discussed.