The central nervous system plays a key role in regulating energy homeostasis and complex inter-related neuronal circuits have therefore developed to regulate feeding behaviour, energy expenditure and peripheral nutrient handling. The hypothalamus has long been recognised as one of the key brain regions involved in such processes receiving and integrating neural, nutrient, and hormonal signals that convey nutritional status and orchestrating appropriate efferent responses. Until recently both the small size of the hypothalamus and the complexity of its neuronal circuitry have made investigations into the precise anatomical and physiological properties of this brain region difficult. However, the advent in recent years of neuron-specific gene manipulation techniques in mice has permitted an increased understanding of the signals, both extra-cellular and intracellular, and the hypothalamic cell types that regulate energy homeostasis. Work from a number of groups has implicated hypothalamic arcuate nucleus pro-opiomelanocortin (POMC) and agouti-related protein/neuropeptide Y (AgrP/NPY) neurons as playing key roles in regulating energy homeostasis. Our work has focussed on the role of two signalling pathways in POMC and AgrP/NPY neurons. The insulin receptor substrate (IRS)/ phosphoinositide- 3-OH kinase pathway mediates the effects of the long-term adiposity hormones, insulin and leptin in peripheral tissues. To establish the role of this pathway in hypothalamic function, we have deleted Irs2 and other signalling components in POMC, AgrP and other neuronal populations. These studies have identified a novel population of neurons in the arcuate nucleus that respond to insulin and play a key role in body weight regulation. The adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status. Accumulating evidence indicates that AMPK regulates whole body energy homeostasis acting in metabolic tissues in response to nutrient and hormonal signals. We have deleted AMPK in POMC and AgrP neurons and these studies have revealed key roles for this pathway in nutrient sensing. We will discuss our findings in detail and review the phenotypes of other transgenic models to provide a current view of the hypothalamic regulation of energy and glucose homeostasis.