OBJECTIVE: This review aimed to examine evidence for the role of hormonal changes in the onset and course of depressive symptomatology and to assess the possible future role of hormonal therapies in the treatment of depression. METHODS: A Medline and PsycINFO search of the literature published between 1965 and 2006 was made of studies of depressive symptoms and hormonal treatment in women at all stages of reproductive life. RESULTS: The cyclic fluctuation of gonadal steroids at menarche coincides with the beginning of gender-based differences in depression rates, which continue throughout reproductive life until menopause. Modifications in hormonal status, whether related to endogenous or exogenous exposure or to hormone deprivation, appear to be associated with affective disorder in a subgroup of women. For these women, a growing body of evidence indicates a biological pattern of vulnerability to mood disorders in response to hormonal fluctuations. This could have three major implications: that women vary in vulnerability to mood disorder when abrupt change in steroid levels occur, that these effects could be cumulative across the female life span, and that women do not arrive at menopause with equal risk of mood disorders or equal susceptibility to the effects of hormonal replacement therapy as has been assumed by current clinical research and practice. CONCLUSION: While hormonal therapies could have positive effects in the treatment and prevention of depressive disorders, further research is required to differentiate hormone-responsive subgroups of women for whom specific hormonal treatments may be most beneficial. To this end, we suggest that a multifactorial model of cumulative vulnerability, which takes into account hormonal exposure throughout life, genetic vulnerability, and environmental factors, may provide better prediction of treatment response.