Carboxylation of pyruvate in the brain was for many years thought to occur only in glia, an assumption that formed much of the basis for the concept of the glutamine cycle. It was shown recently, however, that carboxylation of pyruvate to malate occurs in neurons and that it supports formation of transmitter glutamate. The role of pyruvate carboxylation in neurons is to ensure tricarboxylic acid cycle activity by compensating for losses of α-ketoglutarate that occur through release of transmitter glutamate and GABA; these amino acids are α-ketoglutarate derivatives. Available data suggest that neuronal pyruvate carboxylation is quantitatively important. But because there is no net CO2 fixation in the brain, pyruvate carboxylation must be balanced by decarboxylation of malate or oxaloacetate. Such decarboxylation occurs in both neurons and astrocytes. Several in vitro studies have shown a neuroprotective effect of pyruvate supplementation. Pyruvate carboxylation may be one mechanism through which such treatment is effective, because pyruvate carboxylation through malic enzyme is active during energy deficiency and leads to an increase in the level of dicarboxylates that can be metabolized through the tricarboxylic acid cycle for ATP production. © 2001 Wiley-Liss, Inc.