Schizophrenia is the most severe of the psychotic disorders and has a neurobiological and genetic basis, with environment being a moderating factor but not the primary cause. Numerous studies have demonstrated gender differences in the phenomenology of schizophrenia. This review evaluates three theoretical frameworks that have been developed to explain how gender differences develop in schizophrenia: (1) the neurodevelopmental approach; (2) the structural, neuropathological approach; and (3) the estrogen protection hypothesis. It is concluded that findings are most coherently accounted for by the estrogen protection hypothesis; gender differences in schizophrenia most likely emerge due to the multiple effects of estrogens and their complex interactions with neurotransmitter receptors and in-utero brain development. Women predisposed to schizophrenia appear to be particularly protected from the early-onset form of the illness due to high levels of circulating estrogen, and consequent dopamine suppression. Nonetheless, taken together, the three theoretical frameworks can integrate a wide variety of findings of gender differences in schizophrenia, with compelling evidence existing for all approaches.