Individual cells must carefully regulate their energy flux to ensure nutrient levels are adequate to maintain normal cellular activity. The same principle holds in multicellular organisms. Thus, for mammals to perform necessary physiological functions, sufficient nutrients need to be available. It is more complex, however, to understand how the energy status of different cells impacts on the overall energy balance of the entire organism. We propose that the central nervous system is the critical organ for the coordination of intracellular metabolic processes that are essential to guarantee energy homeostasis at the organismal level. In particular, we suggest that in specific hypothalamic neurons, evolutionarily conserved fuel sensors, such as adenosine monophosphate-activated protein kinase and mammalian target of rapamycin (mTOR), integrate sensory input from nutrients, including those derived from recently ingested food or those that are stored in adipose tissue, to regulate effector pathways responsible for fuel intake and utilization. The corollary to this hypothesis is that dysregulation of these fuel-sensing mechanisms in the brain may contribute to metabolic dysregulation underlying diseases, such as obesity and type 2 diabetes.