Glucose is needed to provide the precursors for the synthesis of neurotransmitters and ATP to enhance their actions, as well as the brain's energy needs that are unrelated to signaling. The cellular partitioning of glucose transport and metabolism is closely linked to local blood flow regulation, and glucose-sensing neurons govern the brain-body nutrient axis. We highlight the multifaceted role and complex regulation of glucose metabolism in the CNS, as well as the physiological and pathophysiological consequences of balanced and disrupted glucose metabolism.