Ghrelin, a peptide hormone first discovered as the endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is predominantly produced and released into the circulation by ghrelin-cells (X/A-like) of the stomach fundus cells. Ghrelin has multiple actions in multiple tissues. In particular, it is the most potent known endogenous orexigenic peptide, and plays a significant role in glucose homeostasis: deletion of the genes encoding ghrelin and/or its receptor prevents high-fat diet from inducing obesity, increases insulin levels, enhances glucose-stimulated insulin secretion and improves peripheral insulin sensitivity. In addition, stimulation of pituitary hormones secretion, regulation of gastric and pancreatic activity, modulation of cardiovascular and hemodynamic activities, cartilage and bone homeostasis, sleep and behavioral influences, and modulation of the immune system, as well as effects on cell proliferation, are other relevant actions of ghrelin. The orexigenic action of ghrelin depends on hypothalamic GHS-R 1a which is expressed in several neuronal populations well known for their involvement in the control of food-intake. The work carried out by different groups over the last few years have uncovered the molecular mechanisms involved in ghrelin orexigenic effect. We have recently reported that central (ICV) administration of ghrelin decreases hypothalamic de novo fatty acid synthesis and increases fatty acid oxidation through selective activation of AMPK and CPT1, respectively. Importantly, the orexigenic effect of ghrelin was mediated by this hypothalamic AMPK/malonyl-CoA/CPT1 axis; in fact, pharmacologic or genetic inhibition of AMPK or CPT1 blunted ghrelin feeding-promoting effects. The molecular details of this interaction will need further investigation, but recent data have demonstrated that they were linked to 1) calmodulin-dependent protein kinase kinase 2 (a upstream kinase of AMPK), and 2) uncoupling protein 2 (UCP2) and hypothalamic free radicals. This, AMPK-driven changes in hypothalamic lipid metabolism will subsequently influence neuropeptide gene-expression possibly through the transcription factor Bsx. Finally, recent evidences indicates that ghrelin acting at central level influence peripheral lipid metabolism in liver and white adipose tissue.