Recent years have seen an impetus in the study for central mechanisms regulating energy balance, and caloric intake possibly as a response to the obesity pandemic. This renewed interest as well as drastic improvements in the tools that are now currently available to neuroscientists, has yielded a great deal of insight into the mechanisms by which the brain regulates metabolic function, and volitional aspects of feeding in response to metabolic signals like leptin, insulin and ghrelin. Among these mechanisms are the complex intracellular signals elicited by these hormones in neurons. Moreover, these signals produce and modulate the metabolism of the cell at the level of the mitochondria. Finally, these signals promote plastic changes that alter the synaptic circuitry in a number of circuits and ultimately affect cellular, physiological and behavioral responses in defense of energy homeostasis. These mechanisms are surveyed in this review.