A historical perspective on estradiol’s enhancement of cognitive function is presented and research primarily in animals but also in humans is reviewed. actions as a neurosteroid to promote memory are discussed. This information is applied to the critical issue URB597 of the current lack of effective hormonal (or other) treatments for cognitive decline associated with menopause and aging. Finally the critical period hypothesis for estradiol effects is discussed along with novel strategies for hormone/drug development. Overall the historical record documents that estradiol positively impacts URB597 some aspects of cognitive function but effective therapeutic interventions using this hormone have yet to be realized. Keywords: Aging Cognition Estradiol Hormone replacement therapy Memory Estrogen receptors Introduction Evidence accumulated over the past 25 years shows that estradiol modulates cognitive function in animals and humans. Modulation begins in utero when estrogens direct sexual differentiation of various brain regions SMARCF1 controlling reproduction and some cognitive functions. Gonadal hormone influences on the nervous system including both estrogens and androgens continue through adolescence and reach their zenith at adulthood when gonadal hormone secretions reach the highest levels. With aging levels of circulating estrogens plummet and appear to contribute to age-related declines in learning and memory function. These hormone-dependent effects on cognition over the lifespan have been attributed to classic genomic mechanisms – hormone binding to specific receptors alterations in gene transcription and the initiation of organ-specific effects in target areas in the brain and peripheral organs. More recently it has also been established that gonadal hormones including estradiol can act at membrane receptors to activate intra-cellular signaling mechanisms which alter cellular function. Moreover there is increasing documentation that gonadal hormones are neurosteroids that is estrogens and androgens are synthesized locally in brain areas and thereby rapidly alter cognition and other neural functions. The physiological functions and implications for this mode of estrogen action are unknown at this time but present a novel area for investigation. Finally in a more global way estradiol also acts indirectly to maintain cognitive functions because it exerts neurotrophic effects within the brain. Thus gonadal hormones estradiol in particular have a rich repertoire of possible mechanisms for influencing cognition. This review provides a brief overview of studies establishing estrogen’s role in promoting cognition primarily in animal models but also in humans and it discusses some data regarding the mechanisms underlying these influences. Newer studies demonstrating how estrogens rapidly alter learning and memory are discussed. The need for exploiting this information is emphasized as it may provide an entirely novel area for therapeutic interventions for memory loss. The failure of current hormone URB597 replacement therapy in post-menopausal women is used to highlight the importance of implementing basic research combined with translational studies in order to develop new treatments and strategies for memory loss. Overall gonadal hormones exert diverse and multi-dimensional influences on some aspects of cognition which are pervasive throughout the lifespan and provide fundamental regulation over higher order neural function i.e. the intellectual/cognitive realms of life. Accumulating but still controversial evidence suggests that estradiol synthesized within the hippocampus and prefrontal cortex URB597 may also contribute to the normal process(es) of memory consolidation. Since the review covers such widespread topics each cannot be discussed in depth but the reader is directed to current reviews. The review concludes that research on estrogens which act as potent hormones neurosteroids and neuromodulators should be expanded in order to take advantage of already demonstrated cognitive enhancements to extend positive hormonal effects throughout the entire lifespan and to determine how estrogens may be of value in mitigating neurodegenerative diseases. More provocatively since intra-neuronally derived estrogens may be involved in the normal process(es) of memory consolidation it is argued that further research may lead to a better understanding of the fundamental processes of learning and memory. The path for achieving these goals is to forge a strong and more informative translation from animal to.