Besides its essential role at regulating neural functions through cyclic GMP, nitric oxide is emerging as an endogenous physiological modulator of energy conservation for the brain. Thus, nitric oxide inhibits cytochrome c oxidase activity in neurones and glia, resulting in down-regulation of mitochondrial energy production. The subsequent increase in AMP facilitates the activation of 5′-AMP-dependent protein kinase, which rapidly triggers the activation of 6-phosphofructo-1-kinase – the master regulator of the glycolytic pathway – and Glut1 and Glut3 — the main glucose transporters in the brain. In addition, nitric oxide activates glucose-6-phosphate dehydrogenase, the first and rate-limiting step of the pentose–phosphate pathway. Here, we review recent evidences suggesting that nitric oxide exerts a fine control of neuronal energy metabolism by tuning the balance of glucose-6-phosphate consumption between glycolysis and pentose–phosphate pathway. This may have important implications for our understanding of the mechanisms controlling neuronal survival during oxidative stress and bioenergetic crisis.