Abstract: Vasoactive intestinal peptide (VIP), secretin and pituitary adenylate cyclase-activating peptide1-38 (PACAP1-38) are widely distributed amphipathic mammalian neuropeptides that exert diverse biological effects in target tissues located distant from their site of release. However, the half-life of exogenously-administered VIP, secretin and PACAP1-38 in the bloodstream is relatively short (minutes) due to rapid degradation and inactivation. This seemingly paradoxical behavior suggests the presence of an innate system(s) that protects the peptides from degradation in vivo. To this end, VIP, secretin and PACAP1-38 express distinct biophysical properties that once released may protect them from degradation in biological fluids. They self-aggregate at low (nanomolar) concentrations and interact avidly with biomimetic phospholipid monolayers and bilayers at physiological concentrations. The latter evokes conformational transition of the VIP, secretin and PACAP1-38 molecules from predominantly random coil in aqueous solution to a-helix, the preferred peptide conformation for receptor interaction, in phospholipids. These features increase peptide stability and amplify bioactivity in vivo. Collectively, these data suggest the presence of an endogenous targeted delivery platform for VIP, secretin and PACAP1- 38. This innate system may constitute a novel molecular recognition paradigm that could also apply to other amphipathic neuropeptides. Importantly, the distinct behavior of VIP, secretin and PACAP1-38 in the presence of phospholipids could be exploited to develop novel, long-acting therapeutic formulations of these peptides.