Tissue-specific expression of the calcitonin (CT) gene can produce either CT or CT gene-related peptide (a-CGRP). The bimodal RNA splicing mechanism acts to produce one of two related prohormone molecules, each of which, through proteolytic processing, generates a family of small secretory peptides. I In thyroidal C cells CT gene expression generates a proCT molecule (13.2 kDa), which is processed to generate CT (3.4 kDa) from its midregion, and two other peptides, one from the amino-and one from the carboxyl-terminal flanking region. In certain regions of the nervous system, a precursor for CGRP (proCGRP) is the predominant CT gene product; processing of this proCGRP (12.5 kDa) generates CGRP (3.8 kDa) from the midregion as well as amino-and carboxyl-terminal flanking peptides analogous to those derived from proCT. The 55-residue" amino-terminal flanking peptide" generated from proCGRP (N-proCGRP) is 90% homologous to the 57-residue peptide generated from proCT (N-proCT). Their first 51 residues are identical, reflecting the fact that the three 5'exons in the CT gene are used in both proCT and proCGRP messenger RNA.'We have shown that the 57-amino acid N-proCT (5 1-residue common region plus 6 unique amino acids) is cogenerated with CT in both normal and transformed C cells, 2 and a recent report suggests that N-proCT is cosecreted in human^.^ Similarly, the 55-amino acid N-proCGRP (common region plus 4 unique amino acids) appears to be cogenerated with CGRP in transformed C cells and can be immunohistochemically localized along with CGRP to specific central and peripheral neuron^.^ Periosteal sensory neurons contain both CGRP and N-proCGRP and may simultaneously release both peptides, since appreciable levels of CGRP have been measured by specific radioimmunoassay in this tissue (unpublished data).