Schizophrenia is a debilitating and pervasive mental illness with devastating effects on psychological, cognitive and social wellbeing, and for which current treatment options are far from ideal. Gender differences and the influence of the female reproductive life cycle on the onset, course and symptoms of schizophrenia and the discovery of estrogen's remarkable psychoprotective properties in animal models led to the proposal of the 'estrogen protection hypothesis' of schizophrenia. This has fueled the recent successful investigation of estradiol as a potential adjuvant therapeutic agent in the management of schizophrenia in women. This review explains the scientific rationale behind the estrogen hypothesis and how it can be clinically utilized to address concerns unique to the care of women with schizophrenia.