The use of animal models to effectively replicate problems such as hormone deficiencies, neurologic diseases, and brain injury and stroke has certainly made a vast contribution to understanding the neuroprotective effects of estrogen in the brain. Studies using gonadectomy procedures followed by 17beta-estradiol replacement have effectively demonstrated the positive effects that estrogen provides in cognitive performance and memory performance tasks. A major problem with such studies is that local brain aromatase (the estrogen-synthesizing enzyme) may still convert locally produced androgens to estrogens. Hence, such "estrogen-deficient" models may not be completely void of estrogen. The generation of the aromatase knockout (ArKO) and estrogen receptor knockout (ERKO) mouse models has enabled researchers to characterize the effects of complete estrogen deficiency within the brain and hence behavior. This review aims to compare and contrast the results of these various mouse models.