Now-a-days, the focus on lactate is due to its being an oxidative substrate for energy metabolism in brain (and other tissues), rather than a useless end product of anaerobic glycolysis. Mounting evidence indicates that lactate does play a major role in aerobic energy metabolism in the brain, the heart, skeletal muscle and possibly in any other tissue and organ. Nevertheless, this evidence has challenged the old concept of lactate being an anaerobic waste product and ignited a fierce debate between the supporters of glucose as the major oxidative energy substrate and those who support lactate as a possible alternative to glucose under certain conditions. While researchers working on energy metabolism in skeletal muscle have taken great strides toward bridging between these two extreme positions, accepting lactate role as an oxidative energy substrate, neuroscientists appear to be somewhat more emotional about their differences and less agreeable. In this paper I have employed findings from research on skeletal muscle along with the existing old and new data on cerebral energy metabolism, to postulate that lactate is the only major product of cerebral (and other tissues) glycolysis, whether aerobic or anaerobic, neuronal or astrocytic, under rest or during activation. Accordingly, lactate is a major, if not the only, substrate used by the mitochondrial tricarboxylic acid cycle. If proven true, this hypothesis should provide a better understanding of the biochemistry and physiology of (cerebral) energy metabolism and hold important implications where neuroimaging is concerned.