Brain function requires oxygen and maintenance of brain oxygenation and substrate delivery is important for normal function. A steady supply of oxygen maintains oxidation of carbohydrates fulfilling the high resting cerebral metabolic rate. The primary metabolic substrates for cerebral metabolism are glucose and lactate. While maybe not a universal observation, during a number of different circumstances exercise becomes associated with central fatigue i.e. an inability of the central nervous system (CNS) to recruit the full motor pool. We have shown that at the same time as the occurrence of central fatigue, marked perturbations in cerebral oxygenation and metabolism occur such as reductions of the cerebral oxygen-to-carbohydrate index (OCI) and the cerebral mitochondrial oxygen tension (PmitoO2). While glucose remains the primary cerebral fuel, lactate’s role in cerebral metabolism during exercise, particularly in hypoxia and at high altitude, is poorly understood. Lactate’s relation to cerebral metabolism has evolved from one of a metabolic waste product to a role in neuro-energetics and control of blood flow. Elevations in systemic arterial lactate during exercise leads to an increased extraction of lactate by the brain, partially fulfilling the glycolytic demands of the citric acid cycle in both normoxia and hypoxia; possibly as a glucose sparring mechanism. Additionally, the brain can both produce and release a substantial amount of lactate in hypoxia, demonstrating not only a shuttling ‘per se’ of lactate between the muscles and brain, but possibly between cerebral neurons and astrocytes. These chances in cerebral metabolic state is associated with reductions maximal handgrip strength. In addition, compared to low intensity cycling exercise without signs of central fatigue or marked cerebral metabolic deviations, exercise in hypoxia reduce PmitoO2 while rating of perceived exertion increased in concert with reduced MVC and voluntary activation. Thus, both exhaustive exercise as well as exercise in hypoxia provokes changes in cerebral oxygenation and metabolism that are similar to those established during exercise in hypoxia with similar indices of central fatigue. Perturbation in cerebral oxygenation and metabolism may therefore play a key role in central fatigue and thereby modulates exercise capacity. Increases in cerebral blood flow during hypoxic exercise, however, fails to maintain adequate cerebral substrate delivery, as the brain appears to fatigue, possibly contributing to a drop in hypoxic exercise performance. Interestingly, attempts to further elevate cerebral blood flow, and consequently substrate delivery via hypercapnia have proven unsuccessful at attenuating the decline in hypoxic exercise performance and the link, if any, between cerebral metabolism and fatigue remains elusive.