Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G-protein-coupled receptor highly expressed in the hypothalamus and pituitary. Using an orphan receptor strategy with a stable cell line expressing GHS-R, we purified endogenous ligands for GHS-R from rat and human stomach and named it "ghrelin," after a word root (ghre) in Proto-Indo-European languages meaning "grow." Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The main active form of rat ghrelin is 28-amino acid peptides with n-octanoyl modification. In rat stomach, a second type of ghrelin peptide was purified, identified as des-Gln14-ghrelin. With the exception of the deletion of Gln14, des-Gln14-ghrelin is identical to ghrelin, retaining the n-octanoic acid modification. Des-Gln14-ghrelin is encoded by an mRNA created by alternative splicing of the ghrelin gene. As in the rat, the major active form of human ghrelin is a 28-amino acid peptide with an n-octanoylated Ser3. However, in human stomach, several minor forms of human ghrelin peptides have been isolated. These can be classified into four groups by the type of acylation observed at Ser3 and into two groups by the amino acids in length. The discovery of ghrelin indicates that the release of GH from the pituitary and appetite stimulation might be regulated by ghrelin derived from the stomach.