Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal peptide/secretin/glucagon family, has an amino acid sequence identity of 68% with vasoactive intestinal polypeptide (VIP). PACAP38, derived from a 176-amino acid precursor (preproPACAP), is a 38-amino acid peptide discovered as an ovine hypothalamic neuropeptide. The amino acid sequence of PACAP is identical in all mammals, and in species such as chicken, frog, salmon, only 1–3 amino acids are different. It is abundant in both the central and peripheral nervous systems and exerts a variety of effects. PACAP in pancreatic islets may play a parasympathetic and sensory neurotransmitter role. PACAP stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations, acting as an insulinotropic factor. PACAP and VIP are two multifunctional neuropeptides modulating innate and adaptive immunity. VIP/PACAP protect T cells from activation-induced cell death through down-regulation of Fas ligand. PACAP immunoreactivity has been shown in nerve fibers innervating the intrapancreatic ganglia as well as the islets of Langerhans in pancreas. PACAP (1-38) is more active than VIP in stimulating adenylate cyclase (EC50=7 nM).