AbstractThe past 20 years have witnessed tremendous advances in the understanding of the central mechanisms regulating food intake and energy balance, possibly in response to the accelerated increase in the incidence of obesity worldwide. 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 and, finally, they promote plastic changes that alter the synaptic circuitry in a number of circuits and ultimately affect cellular, physiological and behavioural responses in defence of energy homeostasis. This chapter provides a synopsis of these advances, leading to the idea of synaptic plasticity as an important factor in the regulation of food intake and energy homeostasis.