Women are at higher risk throughout their reproductive lives than are men for major depression. Numerous molecular and clinical studies have implicated estrogen in modulating brain function including that related to mood. In an attempt to present a conceptual model, the literature of the past 30 years on mood and well-being throughout reproductive life is reviewed as it relates to activity of endogenous, bio-identical, and synthetic estrogen in women. Results indicate that sudden estrogen withdrawal, fluctuating estrogen, and sustained estrogen deficit are correlated with significant mood disturbance. Clinical recovery from depression postpartum, perimenopause, and postmenopause through restoration of stable/optimal levels of estrogen has been noted.