Although there is now a substantial literature on the putative neuroprotective effects of estrogen on cognitive functioning in postmenopausal women, it is replete with inconsistencies. The critical period hypothesis, posited several years ago, attempts to account for the discrepancies in this literature by positing that estrogen treatment (ET) will protect aspects of cognition in older women only when treatment is initiated soon after the menopause. Indeed, evidence from basic neuroscience and from the animal and human literature reviewed herein provides compelling support for the critical period hypothesis. Although it is not known with certainty why estrogen does not protect cognition and may even cause harm when administered to women over the age of 65years, it is likely that the events that characterize brain aging, such as a reduction in brain volume and in neuronal size, alterations in neurotransmitter systems, and a decrease in dendritic spine numbers, form an unfavorable background that precludes a neuroprotective effects of exogenous estrogen on the brain. Other factors that have likely contributed to the discrepancies in the estrogen-cognition literature include differences in the estrogen compounds used, their route of administration, cyclic versus continuous regimens, and the concomitant use of progestins. This critical analysis attempts to define conditions under which ET may protect aspects of cognition in aging women while also considering the cost/benefit ratio for the treatment of women aged 50-59years. Suggestions for specific future research questions are also addressed.