This review highlights recent evidence from clinical and basic science studies supporting the role of estrogen in neuroprotection. Clinical evidence suggests that estrogen exposure reduces the risk and delays the onset and progression of Alzheimer's disease and schizophrenia, and may enhance recovery from traumatic neurological injuries such as stroke. Basic science studies show that exogenous estradiol decreases the response to various forms of insult, and the brain itself upregulates both estrogen synthesis and estrogen receptor expression at sites of injury. Estrogen may play a protective role through several mechanisms, including alterations in cell survival, axonal sprouting, regenerative responses, enhanced synaptic transmission, and neurogenesis. Some of these effects are independent of classical nuclear estrogen receptors and involve unidentified membrane receptors, direct modulation of neurotransmitter receptor function, or the known anti-oxidant activities of estrogen. Other neuroprotective effects depend on the classical nuclear estrogen receptor, altering the expression of estrogen-responsive genes involved in apoptosis, axonal regeneration, or general trophic support. The potential clinical benefits of estrogen treatment for enhancing cognitive function may outweigh the associated central and peripheral risks. Future research should focus on optimizing ligand and dose, modulating neurotrophin and neurotrophin receptor expression, and understanding the interaction of estrogen with other trophic factors and signaling pathways.This review highlights recent evidence from clinical and basic science studies supporting the role of estrogen in neuroprotection. Clinical evidence suggests that estrogen exposure reduces the risk and delays the onset and progression of Alzheimer's disease and schizophrenia, and may enhance recovery from traumatic neurological injuries such as stroke. Basic science studies show that exogenous estradiol decreases the response to various forms of insult, and the brain itself upregulates both estrogen synthesis and estrogen receptor expression at sites of injury. Estrogen may play a protective role through several mechanisms, including alterations in cell survival, axonal sprouting, regenerative responses, enhanced synaptic transmission, and neurogenesis. Some of these effects are independent of classical nuclear estrogen receptors and involve unidentified membrane receptors, direct modulation of neurotransmitter receptor function, or the known anti-oxidant activities of estrogen. Other neuroprotective effects depend on the classical nuclear estrogen receptor, altering the expression of estrogen-responsive genes involved in apoptosis, axonal regeneration, or general trophic support. The potential clinical benefits of estrogen treatment for enhancing cognitive function may outweigh the associated central and peripheral risks. Future research should focus on optimizing ligand and dose, modulating neurotrophin and neurotrophin receptor expression, and understanding the interaction of estrogen with other trophic factors and signaling pathways.