That gonadal steroids influence the limbic system and that they affect neurotransmitter activity is undisputed. Because of these known actions, and because ET and HT alleviate hot flushes and resultant sleep disturbances, they may improve mood and sense of well-being in healthy climacteric women. However, estrogen plus progestin did not decrease depressive symptoms in the WHI, the largest double-blind, placebo-controlled trial of hormone replacement yet performed. In addition, although several studies have suggested efficacy in this regard, neither ET nor HT has been proved to be therapeutic for major depression in perimenopausal and menopausal women. Certainly, further studies are needed on the potential of estrogen as an antidepressant. Based on current evidence, however, one cannot prescribe ET or HT as primary treatment for major depression in good conscience. When treating patients far this serious problem, one cannot rely on theory and the desire that it be borne out. As Sigmund Freud wrote: "Thus we call a belief an illusion when a wish-fulfillment is a prominent factor in its motivation, and in doing so we disregard its relation to reality, just as the illusion itself set, no store by verification". Since the initial publication of the results of the WHI, clinicians have learned to be cautious when making decisions about therapy that has not been proved in randomized controlled trials. In addition, attention has shifted away from potential global effects of ET and HT toward more specific management of each specific clinical sequela of menopause. If major depression is to be addressed in this way, SSRIs become first-line therapy, with TCAs considered second-line because of reduced tolerability. ET and HT may be added separately as appropriate, and may be helpful on an individual basis. Indeed, treatment for major depression in any person, male or female, at any age, is best chosen based on life situation and the neuropsychology of the condition, and not based on gender alone.