Sex steroids modulate brain function at all developmental stages of life. This article focuses on the role of sex steroids after menopause with the intent of addressing the question whether or to what extent sex steroids, particularly estrogenic agents, are neuroprotective for the aging brain of women. The rationale for delving into this complicated topic is that the information and perspective so acquired will aid physicians in counseling surgically and naturally menopausal women about their therapeutic options. Whereas we review and synthesize relevant data from monkey, other animal, cellular, and molecular studies, the emphasis is on human studies and reconciling the disparate evidence. Although the knowledge gaps are considerable, available evidence suggests that extended use of non-oral estradiol is a reasonable course of action if the woman to be treated has a relatively low risk for cardiovascular disease and venous thromboembolism or a high concern about developing dementia. It is important to emphasize that estradiol may negatively impact an already unhealthy individual and yet synergize other health-promoting behaviors such as good nutrition, exercise, and stress reduction in a relatively healthy individual.