Recent findings from the Women's Health Initiative (WHI) suggest that hormone therapy (HT) and estrogen therapy (ET) increase the risk of stroke in postmenopausal women. These results were unexpected based upon many previous clinical, observational, and epidemiological studies and a large body of evidence that come from studies performed in animal models. Before we assume that these results are widely applicable to other hormone preparations and to all older postmenopausal women, we should consider whether the particular hormone preparations, the doses that were used, the age of the women, the length of time that they were postmenopausal prior to the initiation of treatment, and/or their health status may have been important factors in the results of this clinical trial. We believe that results of studies using animal models provide insights into why the result of the WHI should have been expected. Furthermore, results of basic science studies provide a strong rationale for the design of future clinical studies that will more accurately test the effects of ET/HT on the risk and outcomes of cerebrovascular stroke in middle-aged perimenopausal and early postmenopausal women. We will review data, predominantly from our laboratory, gathered over the past six years that lead us to this conclusion.