The hypothalamus is a specialised area in the brain that integrates the control of energy homeostasis, regulating both food intake and energy expenditure. The classical theory for hypothalamic feeding control is mainly based on the relationship between peripheral signals and neurotransmitters/neuromodulators in the central nervous system. Thus, hypothalamic neurons respond to peripheral signals, such as hormones and nutrients, by modifying the synthesis of neuropeptides. Despite the well-established role of these hypothalamic networks, increasing evidence indicates that the modulation of lipid metabolism in the hypothalamus plays a critical role in feeding control. In fact, the pharmacologic and genetic targeting of key enzymes from these pathways, such as AMP-activated protein kinase, acetyl-CoA carboxylase, carnitine palmitoyltransferase 1, fatty acid synthase, and malonyl-CoA decarboxylase, has a profound effect on food intake and body weight. Here, we review what is currently known about the relationship between hypothalamic lipid metabolism and whole body energy homeostasis. Defining these novel mechanisms may offer new therapeutic targets for the treatment of obesity and its associated pathologies.