This chapter discusses pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). PACAP and VIP are neuropeptides implicated in neuroprotection, and they are both widely distributed throughout the body. VIP neuroprotection has been associated with glial cell interaction to activate the synthesis and secretion of neuroprotective proteins. The primary working hypothesis is that VIP (at low, probably physiological, concentrations) stimulates glial cells to release multiple neuroprotective substances, including a complex array of cytokines and growth factors. VIP, PACAP, and the respective G-protein-coupled receptors modulate effects on neuroprotection. Some of these effects may be associated with changes in the cytoskeletal network that offer cellular protection or activity in the brain. Activity-dependent neuroprotective protein (ADNP) was discovered as a VIP/ PACAP-regulated protein that is essential for brain formation. A downstream derivative of VIP/PACAP action, NAP is a very short 8-amino-acid peptide derived from ADNP that provides neuroprotection. NAP has been selected based on potent neuroprotective properties and brain bioavailability for further clinical development.