The ghrelin-ghrelin receptor system is one of the most important mechanisms regulating energy balance and metabolism. Among other actions, central and peripheral administration of ghrelin increases food intake and adiposity. During the last years, many efforts have been made in the investigation of the cellular and molecular mechanisms modulating the effects of ghrelin. One particularity of this peptide hormone is its acylation at serine-3 with an eight-carbon fatty acid (octanoate), which confers its biological activity. Recent reports have demonstrated that the ghrelin O-acyltransferase (GOAT) is the enzyme that catalyzes ghrelin octanoylation. Therefore, all questions concerning the posttranslational acylation of ghrelin are of great interest for the complete understanding of this system. In this review, we summarize the discovery and characterization of GOAT, and remark the importance of GOAT as a novel and potential target that regulates the biological actions of ghrelin, revealing several therapeutical possibilities for the treatment of the metabolic syndrome.