The vasoactive intestinal peptide (VIP) and the pituitary adenylate cylaseactivating polypeptide (PACAP) belong to a superfamily of peptide hormones that include glucagon, secretin and growth hormone releasing hormone. The effects of VIP and PACAP are mediated by three G-protein coupled receptors, VPAC1, VPAC2 and the PACAP receptor (also designated PAC1-R). The VPAC receptors have equal affinities for VIP and PACAP, which stimulate the activation of adenylyl cyclase. Both VPAC1, a 47 kDa protein, and VPAC2, a 65 kDa protein, are abundantly expressed in brain and T cells, where they modulate neuronal differentiation and T cell activation, respectively. The PACAP receptor is a seven transmembrane protein that produces at least eight isoforms by alternative splicing. Each isoform is associated with a specific signaling pathway and a specific expression pattern. The PACAP receptor, which is thought to play an integral role in brain development, preferentially binds PACAP in order to stimulate a cAMP-protein kinase A signaling pathway.