Glucose-dependent insulinotropic polypeptide (GIP; gastric inhibitory polypeptide) is a 42 amino acid hormone that is produced by enteroendocrine K-cells and released into the circulation in response to nutrient stimulation. Both GIP and glucagon-like peptide-1 (GLP-1) stimulate insulin secretion in a glucose-dependent manner and are thus classified as incretins. The structure of mammalian GIP is well conserved and both the N-terminus and central region of the molecule are important for biological activity. Following secretion, GIP is metabolized by the endoprotease dipeptidyl peptidase IV (DPP-IV). In addition to its insulinotropic activity, GIP exerts a number of additional actions including promotion of growth and survival of the pancreatic beta-cell and stimulation of adipogenesis. The brain, bone, cardiovascular system, and gastrointestinal tract are additional targets of GIP. The GIP receptor is a member of the B-family of G protein-coupled receptors and activation results in the stimulation of adenylyl cyclase and Ca(2+)-independent phospholipase A(2) and activation of protein kinase (PK) A and PKB. The Mek1/2-Erk1/2 and p38 MAP kinase signaling pathways are among the downstream pathways involved in the regulation of beta-cell function. GIP also increases expression of the anti-apoptotic Bcl-2 and decreases expression of the pro-apoptotic Bax, resulting in reduced beta-cell death. In adipose tissue, GIP interacts with insulin to increase lipoprotein lipase activity and lipogenesis. There is significant interest in potential clinical applications for GIP analogs and both agonists and antagonists have been developed for preclinical studies.