The interaction between astrocytes and neurons is examined from the standpoint of glutamate and glutathione (GSH) metabolism. These examples are outlined to provoke a reformulation of concepts of the inter-dependence between these 2 cell types, not only in terminating excitotoxicity, but also in assuring proper energetics and neuromodulation by astrocytic removal of glutamate via the astrocyte-specific glutamate transporters, GLT1 and GLAST. In addition, the role of astrocytes in the synthesis of neuronal GSH is detailed. The neuron-astrocyte interaction permits widely divergent aspects of brain energetics and modulation, and undoubtedly brain pathology where the functional unit is altered. Testing the developmental effects of compounds on this interaction is warranted and likely to establish the mechanisms by which it is compromised in a variety of disease states.