Randomized controlled trials (RCTs) and observational and longitudinal studies provide positive, albeit, inconsistent evidence that estrogen might protect against cognitive decline in postmenopausal women. The fact that the Women's Health Initiative Memory Study (WHIMS), the largest RCT to date, failed to find that estrogen therapy (ET) had a protective effect against cognitive aging led to the formulation of the critical period hypothesis which holds that ET will effectively protect against memory decline when it is initiated around the time of menopause but not when considerable time has elapsed since the menopause. Evidence from basic neuroscience, and from rodent, nonhuman primate, and human studies that supports this theory is presented. Although much work remains to be done on the timing of initiation of treatment, on the most effective hormonal compounds and on their routes of administration, the hope is that, eventually, hormonal treatments may be able to attenuate or prevent the decline in aspects of cognition that occur with normal aging.