Vasoactive intestinal peptide (VIP) and pituitary adenylyi cyclase-activating peptide (PACAP) are homologous mediators that are released from cholinergic, nonadrenergic noncholinergic, and other neurons. They are recognized by members of a subfamily of G protein-coupled receptors. VIP and PACAP are distributed widely, but with anatomical peaks, in the nervous and endocrine systems, lungs, intestines, and immune organs. Their early appearance in embryo-genesis and the deleterious effects of pharmacological antagonism in utero both suggest that VIP and PACAP are critical mediators of development. In adult mammals, VIP and PACAP normally have potent neural, endocrine, other physiological, and immune effects and potential pathological roles in esophageal achalasia, Hirschsprung's disease of the colon, cystic fibrosis, diabetes, and asthma.