Estrogens are now recognized as potent neuroprotectants in a variety of in vitro and in vivo model for cerebral ischemia. These protective effects of estrogens are seen in neurons, astrocytes, microglia and vascular endothelial cells and result in a profound protection of the brain during stroke. Herein, we provide a thesis that indicates that the protective effects of estrogens during stroke may be a combined effect on multiple targets of the neurovascular unit (NVU) through a fundamental protective effect of estrogens on the subcellular organelle that defines the fate of cells during insults, the mitochondria. By protecting mitochondria during insult, estrogens are able to reduce or eliminate the signal for cellular necrosis or apoptosis and thereby protect the NVU from ischemia/reperfusion. In this context, estrogens may be unique in their ability to target the cellular site of initiation of damage during stroke and could be a central compound in a multi-drug approach to the prevention and treatment of brain damage from stroke.