Treatment too far past the menopausal transition may have less beneficial effect. The beneficial effect of estrogen upon cognition is not restricted to humans, as it is also observed in lower species. For instance, cyclic estrogen replacement has been shown to significantly improve cognitive function in ovariectomized female monkeys [217]. Furthermore, estrogen replacement has been shown to improve the performance of ovariectomized rats in memory tasks such as radial mazes and water mazes [218–225], as well as in the operant alternation task [226,227] and the active avoidance task [228]. A number of studies have also provided evidence that estrogen can enhance working memory in ovariectomized animals [229–232]. The potential site(s) of action and underlying mechanisms for estrogen beneficial effects on cognition will be reviewed in the subsequent sections.