Lactate has been considered for a long time as a metabolic waste and/or a sign of hypoxia in the central nervous system. Nevertheless, clear evidence that lactate can constitute an adequate energy substrate for brain tissue has been provided as early as in the 1950s with the pioneering work of McIlwain in brain slices. Over the years, several studies using different approaches have confirmed that lactate is efficiently oxidized by brain cells in vitro. Moreover, lactate has been shown under certain circumstances to have a neuroprotective effect and support neuronal activity. Similar confirmation of lactate utilization in vivo as well as putative neuroprotection in various excitotoxic models has been provided. Lactate was even shown to restore cognitive performance upon an hypoglycemic episode in humans. More recently, it was proposed that lactate could be produced by astrocytes and released in the extracellular space to form a pool readily available for neurons in case of high energy demands. Several elements support the concept of a lactate shuttle between astrocytes and neurons in the central nervous system. Among them, the description of specific monocarboxylate transporters found on both astrocytes and neurons is an important observation consistent with this concept. Interestingly, lactate shuttles between different cell types within the same organ have been described outside the central nervous system, notably in muscle and testis. Thus, lactate is emerging as a valuable intercellular exchange molecule in different systems including the brain where it might be an essential element of neuron-glia metabolic interactions.