Ghrelin is a 28 amino acid peptide hormone first identified as a growth hormone (GH) stimulating peptide which is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a) [30]. Ghrelin has a unique acylation on its serine 3 residue which is required for activation of GHS-R1a [31]. Both ghrelin and des-acylated (lacks the serine 3 acylation) are found in circulation. Shortly after its discovery ghrelin administration was demonstrated to acutely stimulate feeding and chronically induce adiposity in rodents [38,46,51]. These effects were thought to be mediated via hypothalamic neuropeptide Y (NPY)/agouti related protein (AgRP) neurones [29,38]; a population of neurones known to stimulate feeding. In humans it was shown that circulating ghrelin levels rise before a meal and are suppressed post-prandially [12,47]. Subsequently the first study investigating ghrelin administration in man reported a potent stimulation of appetite [50]; findings that have since been replicated many times. Together these data led to the hypothesis that ghrelin acts as a hunger signal initiating the onset of meals. Antagonism of the ghrelin system therefore appeared an attractive target for anti-obesity therapies. This led to much research and investment aimed at developing anti-obesity drugs designed to antagonize the ghrelin system. Despite this early optimism a ghrelin based treatment for obesity has yet to emerge. This review analyzes the role of the ghrelin system in appetite regulation in humans and assesses its potential as a target for obesity therapies.