Adult mammals do a masterful job of matching caloric intake to caloric expenditure. To accomplish this, the central nervous system (CNS) must be able to monitor the status of peripheral energy stores and ongoing fuel availability. Recent observations support the hypothesis that ongoing fuel availability can be monitored directly in the CNS by mechanisms that extend beyond the sensing of glucose (the primary neuronal fuel). Questions remain as to how signals from stored and available fuel are integrated, and it will be vital to answer these key neuroscience questions to develop biological therapies to curb the growing human and monetary costs of obesity.