Identification and characterization of the cDNA encoding rat neuropeptide Y revealed the nucleotide sequence coding for a 98-amino acid precursor. The deduced amino acid sequence for rat neuropeptide Y is identical to the human peptide and is highly homologous to avian pancreatic polypeptide. The tertiary structure of avian pancreatic polypeptide has been previously derived from crystallographic data by Blundell and coworkers. The homology between neuropeptide Y and avian pancreatic polypeptide preserves all of the residues essential for the maintenance of the tertiary structure. Thus, it has been possible to compute a three-dimensional model of the mammalian neuropeptide, neuropeptide Y, based on the known structure of the avian homologue. This model suggest that neuropeptide preserves a compact tertiary structure characterized by extensive hydrophobic interactions between an N-terminal polyproline-II-like helix and a C-terminal alpha-helix. The model has been used to identify amino acids residing in key positions within this structure and, thereby, to direct future analysis of neuropeptide Y structure-function relationships.