The male/female differences that have been described in schizophrenia are important because they may ultimately shed light on factors that mediate the expression of schizophrenic illness. The hypothesis of this article is that estrogens, either directly or indirectly, modify symptom expression and account for many of the observed gender differences. The role of sex hormones is divided into organizational and activational effects. Organizational effects take place during a critical period in fetal life and put a permanent stamp on the developing brain. Activational effects are the direct influences of circulating hormones that appear when hormonal levels rise, and wane when hormonal levels drop. Because levels of sex hormones in adult women fluctuate during the menstrual cycle, cyclic effects of high and low female hormones may induce specific responses by the adult female brain. All these effects have implications for genetic, environmental, pharmacological, neurocognitive, clinical, and epidemiological research in schizophrenia.