Blockade of renin angiotensin system (RAS) is effective to prevent onset of stroke. However, the detailed mechanism is still an enigma. Here we discuss about the role of RAS in brain damage after stroke and cognitive decline associated with metabolic syndrome. Increase in angiotensin II in the brain enhanced ischemic damage after middle cerebral artery occlusion. On the other hand, temporal blockade of RAS even after cessation of angiotensin II type-1 receptor blocker (ARB) treatment prevented brain damage with increase capillary density in the brain. Angiotensin II type-2 (AT2) receptor signaling contributes to protect brain via enhancement of neural differentiation. Moreover, AT2 receptor signaling in the other tissue also contributes to brain protection. For example, bone marrow stromal cells (MSCs) have been expected to improve the brain damage by transplantation after stroke; however, MSCs prepared from AT2 receptor deficient mice could not improve survival rate in mice after ischemia-reperfusion injury. Finally, cognitive impairment observed in type 2 diabetic model mice and mice fed with metabolic syndrome prone diet was prevented by treatment with nonhypotensive dose of ARBs. These results suggest that regulation of RAS by ARB could be a therapeutical benefit to prevent brain damage in patients with hypertension.