Evidence is presented indicating a role for estrogen in the function and maintenance of the aging brain. Based on complementary data that estrogen regulates the function of the immune--brain barrier, the hypothesis is presented that estrogen contributes to brain homeostasis via regulation of microglial activation, enabling immune-privileged status in the brain. Diminished estrogen levels during the menopause compromise the immune--brain barrier fostering inflammatory processes in the brain. This has potentially lethal consequences for brain cells, and may contribute to brain pathologies such as Alzheimer's disease.