Pituitary adenylate cyclase-activating polypeptide (PACAP) is an ancient neuropeptide that predates the evolution of vertebrates. While PACAP acts on multiple target organs and has multiple roles in development, neuronal network function and metabolic homeostasis, it also appears to play an important role in the control of breathing. Mice lacking PACAP die suddenly in the second week of life, a phenotype that is exaggerated by mild thermal stress and bares resemblance to human SIDS. Here we discuss several hypotheses as to why PACAP signaling is important for neonatal survival, focusing on data demonstrating an important role in the control of breathing. We review data suggesting that (a) breathing and respiratory chemosensitivity is blunted in PACAP-deficient mice; (b) PACAP plays an important role in protecting neonatal breathing during thermal stress; and (c) PACAP-signaling occurs in a number of loci important for respiratory control including the carotid bodies (the main peripheral respiratory chemoreceptors) and nuclei in the hypothalamus, pons and medulla, as well as pathways involved in setting sympathetic-parasympathetic tone. Whether PACAP gene abnormalities contribute to Sudden Infant Death Syndrome (SIDS) by reducing respiratory system efficacy during environmental stress remains unanswered.