In this article, David Nicholls and David Attwell describe recent advances in our understanding of the mechanisms by which excitatory amino acids are released from cells, and of the way in which a low extracellular glutamate concentration is maintained. Glutamate can be released from cells by two mechanism: either by Ca2(+)-dependent vesicular release or, in pathological conditions, by reversal of the plasma membrane uptake carrier. The contrasting pharmacology and ionic dependence of the glutamate uptake carriers in the vesicle membrane and in the plasma membrane explain how glutamate (but probably not aspartate) can function as a neurotransmitter, and why the extracellular glutamate concentration rises to neurotoxic levels in brain anoxia.