In mammals, alternative splicing of the calcitonin gene generates two distinct peptides: calcitonin (CT), synthesised in the thyroid C cells and involved in the regulation of calcium metabolism, and calcitonin gene-related peptide (CGRP), brain neuromediator synthesised in the peripheral and central nerves. CGRP is well represented and molecularly conserved during evolution whereas CT has not been detected in any of the invertebrates analysed so far. In order to better understand the evolution of this CT/CGRP peptide family we reviewed the major data concerning its evolution from the literature and our recent data obtained in models of teleosts and cephalopod molluscs. The presence of both CGRP-like molecules and its specific bindings sites in the central nervous system of eel, cuttlefish and nautilus, suggests that the brain neurotransmitter role of CGRP could represent an ancient role in metazoa, already present in cephalopods and conserved among vertebrates, as still observed in mammals. In contrast, the presence of CGRP specific binding sites, and not the peptide itself, in the gills suggests an endocrine role for CGRP, in cephalopods and teleosts, that may have been lost during the evolution of the tetrapod lineage. These data, and the absence of CT-like molecules that we observed in cephalopods, support the hypothesis that CGRP represents the ancestral molecule of the CT/CGRP family, appeared in metazoa before the vertebrate emergence. The distinction between CT and CGRP receptors appears to be an event posterior to the emergence of ecdysozoan and lophotrochozoan protostomes, probably in relation to the CT appearance. The evolution of the CT/CGRP peptide family is probably similar to the evolution of the CT/CGRP receptor family. In fact, the genic duplication that induced the appearance of the two separate molecules, CT and CGRP, may constitute an event close to that, which induced the appearance of the two specific receptors. These events remain to be further studied in order to better understand the peptide and receptor evolution of the CT/CGRP family.