Findings regarding post-menopausal effects of estrogen (E2) on women's cognition are divergent. Observational studies of post-menopausal women and a large body of basic research indicates E2 is able to reduce cognitive decline. For instance, the Women's Health Initiative Study, which examined women 64 years or older who were randomly assigned to receive hormone-replacement therapy (HRT), found a two-fold increase in dementia diagnoses among this population. Since then, several theories have emerged to explain such discrepant findings, such as the variety of E2-replacements available, the timing after menopause when HRT is initiated, and/or the effects of other steroid hormones (e.g. progestins, androgens, etc). In fact, considerably less focus has been paid to the potential synergistic input E2 may require from progestins and/or androgens in mediating these processes. Due to the increasing peri- to post-menopausal population, and the ambiguous findings from bench to clinical trials, this review will focus on a synthesis of the available information regarding findings from animal and human studies in terms of different HRT options and their subsequent interactions in the brain, effects on womens' cognitive abilities and risk of developing a neurodegenerative disease.