Gastric inhibitory polypeptide (GIP), or glucose-dependent insulinotropic peptide, is released from endocrine cells in the small intestine after meals. It is involved in several facets of the anabolic response and is thought to be particularly important in stimulating insulin secretion. We have cloned, functionally expressed, and mapped the distribution of the receptor for GIP. It is a member of the secretin-vasoactive intestinal polypeptide family of G-protein-coupled receptors. When expressed in tissue culture cells, it stimulates cAMP production (EC50 0.3 nM) and also increases intracellular calcium accumulation. GIP receptor mRNA is present in the pancreas as well as the gut, adipose tissue, heart, pituitary, and inner layers of the adrenal cortex, whereas it is not found in kidney, spleen, or liver. It is also expressed in several brain regions, including the cerebral cortex, hippocampus, and olfactory bulb. These results suggest that GIP may have previously undescribed actions. GIP receptor localization in the adrenal cortex suggests that it may have effects on glucocorticoid metabolism. Neither GIP nor its effects have been described in the central nervous system, and mRNA for the known peptide ligand for the receptor cannot be detected in the brain by in situ hybridization or polymerase chain reaction. This suggests that a novel peptide may be present in the brain.