Vasoactive intestinal polypeptide (VIP) has a variety of physiological effects. Pharmacological evidence suggesting that VIP acts via multiple receptors has been confirmed by the cloning of two VIP receptors (VIP1 and VIP2) with very different amino acid sequences. At both the VIP1 and the VIP2 receptor VIP, PHI, PACAP38, and PACAP27 have similar potency to each other. Only the VIP1 receptor is activated by secretin. The messenger RNAs (mRNAs) for the two receptors have completely different distributions as mapped by in situ hybridization histochemistry. VIP1 receptor mRNA is predominantly found in the lung, small intestine, thymus, and within the brain in the cerebral cortex and hippocampus. VIP2 receptor mRNA is present in a number of areas where VIP acts but VIP1 receptor mRNA is not present, including the stomach and testes. In the CNS VIP2 receptor mRNA is exclusively present in areas associated with neuroendocrine function, including several hypothalamic nuclei. In the periphery, it is also present in the pituitary and in pancreatic islets.