Mast cells (MCs) are perivascularly located resident cells of hematopoietic origin, recognized as effectors in inflammation and immunity. Their subendothelial location at the boundary between the intravascular and extravascular milieus, and their ability to rapidly respond to blood- and tissue-borne stimuli via release of potent vasodilatatory, proteolytic, fibrinolytic, and proinflammatory mediators, render MCs with a unique status to act in the first-line defense in various pathologies. We review experimental evidence suggesting a role for MCs in the pathophysiology of brain ischemia and hemorrhage. In new-born rats, MCs contributed to brain damage in hypoxic-ischemic insults. In experimental cerebral ischemia/reperfusion, MCs regulated permeability of the blood-brain barrier, brain edema formation, and the intensity of local neutrophil infiltration. MCs were reported to play a role in the tissue plasminogen activator-mediated cerebral hemorrhages after experimental ischemic stroke, and to be involved in the expansion of hematoma and edema following intracerebral hemorrhage. Importantly, the MC-stabilizing drug cromoglycate inhibited MC-mediated adverse effects on brain pathology and improved survival of experimental animals. This brings us to a position to consider MC stabilization as a novel initial adjuvant therapy in the prevention of brain injuries in hypoxia-ischemia in new-borns, as well as in ischemic stroke and intracerebral hemorrhage in adults.