An increasing number of regulatory peptide genes are known to be transcribed in neuroendocrine cells of the intestine and neurons of the central and peripheral nervous system. The discovery of the expression of peptide hormone genes in the nervous system has led to the suggestion that these peptides may function as neurotransmitters, neuromodulators, and releasing or inhibiting factors in different regions of the brain. Glucagon and the glucagon-like peptides are derived from proglucagon in the pancreatic islets and intestine. A role for these peptides in the central nervous system has been proposed, but evidence for the biosynthesis of proglucagon in brain has been lacking. We now report that the glucagon gene is expressed in the brainstem and hypothalamus and that a glucagon mRNA transcript identical to that produced in pancreas and intestine gives rise to proglucagon-related peptides in the brain.