A number of clinical trials associated with the Women’s Health Initiative (WHI) have assessed the potential benefits of hormone replacement therapy (HRT) for protection against the development of cardiovascular disease and memory loss in menopausal women. The results of the WHI Memory Study suggest that HRT increases the risk of stroke and dementia in menopausal women. This finding has called into question the results of hundreds of basic science studies that have suggested that estrogen could protect brain cells from damage and improve cognition. A number of researchers have argued that inappropriate formulation, improper dosing, a limited study population, and poor timing of administration likely contributed to the reported findings from the clinical trial. Regarding appropriate formulation, it has been suggested that interactions between estrogen and other hormones should be considered for further investigation. A review of the literature has led us to conclude that a thorough investigation into such hormonal interactions is warranted. We hypothesize that the increased risk of cerebrovascular disease observed in menopausal women may, in part, be due to changes in the circulating levels of melatonin and estrogen and their modulatory affects on many relevant endothelial cell biological activities, such as regulation of vascular tone, adhesion to leukocytes, and angiogenesis, among others. Our hypothesis is supported by numerous studies demonstrating the reciprocal inhibitory effects of melatonin and estrogen on vascular tone, neuroprotection, and receptor expression. We believe that a thorough analysis of the distribution, localization, expression, quantification, and characterization of hormonal receptor subtypes, as well as changes in structural morphology in diseased and normal, healthy cerebrovascular tissue, will substantially aid in our understanding of the effects of HRT on the cerebrovascular circulation. The application of new molecular biological techniques such as tissue microarray analysis, gene and protein arrays, and multi-photon confocal microscopy may be of tremendous benefit in this regard.