To understand and intervene in neuronal cell death, intensive investigations have been directed at the discovery of intracellular and extracellular factors that provide natural neuroprotection. This goal has fundamental importance for both rational strategies for the treatment of neurodegenerative diseases and also the delineation of molecular mechanisms that regulate nervous system differentiation and growth. We have discovered a potential interface among these fields of research with activity-dependent neurotrophic factor (ADNF), a protein containing sequence homologies to intracellular stress proteins that is found in the extracellular milieu of astroglial cells incubated with the neuropeptide vasoactive intestinal peptide (VIP). Femtomolar concentrations of ADNF and a short peptide sequence derived from it (a peptidergic active site) protected neurons from death associated with a broad range of toxins, including those related to Alzheimer's disease, the human immunodeficiency virus, excito-toxicity, and electrical blockade. Because the activity of the protein was mimicked by a short peptide fragment, this peptide is now proposed as a lead compound for drug development against neurodegeneration.