Background: Ghrelin, a unique 28 amino acid peptide hormone secreted by the gastric X/A like cells, is an endogenous ligand of the growth hormone secretagogue receptor (GHSR). Ghrelin-GHSR signaling has been found to exert various physiological functions, including stimulation of appetite, regulation of body weight, lipid and glucose metabolism, and increase of gut motility and secretion. This system is thus critical for energy homeostasis. Objective: The objective of this review is to highlight the strategies of ghrelin-GHSR based intervention for therapy of obesity and its related metabolic diseases. Results: Therapeutic strategies of metabolic disorders targeting the ghrelin-GHSR pathway involve neutralization of circulating ghrelin by antibodies and RNA spiegelmers, antagonism of ghrelin receptor by its antagonists and inverse agonists, inhibition of ghrelin O-acyltransferase (GOAT), as well as potential pharmacological approach to decrease ghrelin synthesis and secretion. Conclusion: Various compounds targeting the ghrelin-GHSR system have shown promising efficacy for intervention of obesity and relevant metabolic disorders in animals and in vitro. Further clinical trials to validate their efficacy in human being are urgently needed.