l-Glutamate (Glu) homeostasis in brain extracellular fluids and its maintenance at low micromolar concentrations in the face of the extremely high Glu concentrations present in brain cells and synaptic vesicles have been commonly attributed to the very effective action of glutamate transporters present on neuronal and glial cells. This view however does not take into account the fact that the brain is highly vascularized and that the vasculature harbors a high density of glutamate transporters. In this article, we review the accumulated data establishing the existence of an efflux of excess Glu from brain extracellular fluids into blood. We describe plausible mechanisms accounting for this efflux and present evidence that the brain-to-blood Glu efflux is modulated by blood Glu levels and can be accelerated by blood Glu scavenging. The latter procedure shown here to afford brain neuroprotection in a rat model of closed head injury could be applicable, as a first-line therapy, in the various acute brain insults characterized by excess Glu in brain fluids.