Calcitonin gene-related peptide (CGRP) is a recently characterized neuroactive substance that is expressed in a large proportion of small- to medium-diameter sensory ganglion neurons whose central terminals lie in the superficial spinal and medullary dorsal horn. This restricted distribution within the peripheral nervous system suggests a prominent role for the peptide in nociceptive processing. The mammalian tooth pulp, which receives a relatively homogeneous afferent input from thin (putative nociceptive) fibers originating from this subpopulation of trigeminal ganglion cells, thus affords an ideal target zone in which to examine peripheral nociceptive mechanisms. The large percentage of these neurons displaying CGRP-like immunoreactivity (CGRP-LI) furthermore provides a valuable tool to study its thin-fiber afferent innervation. CGRP-LI has been localized within intact, decalcified specimens of rat, cat, monkey, and human teeth and associated dental structures. A remarkably robust CGRP-LI innervation of molar pulp and dentin was revealed in all species, with fibers coursing both in fascicles and individually, in variable relation to blood vessels and pulpal stroma. Our methods enabled tracing of a large number of axons through Raschkow's plexus and odontoblast layer into dentinal tubules. Paralleling anterograde axonal transport studies, a greater share of fibers was found in coronal vis-à-vis radicular dentin. In the rat, this fiber pattern stood in contrast both to incisor dentin, which appeared devoid of CGRP-LI, and to the abundant labeled axons in gingiva and periodontal tissues. Surgical deafferentation of rat mandible resulted in widespread depletion of CGRP-LI, while superior cervical ganglionectomy was without effect, confirming the sensory nature of the CGRP-LI fibers. Neonatal capsaicin treatment greatly attenuated the immunostaining, providing evidence for CGRP-LI localization in chemosensitive unmyelinated afferents. The great density of CGRP-LI axons demonstrated is considered in contrast to the restricted range and extent of sensory stimuli to which teeth are presumably subjected, and in relation to the diverse ongoing trophic, regulatory, and reparative processes in tooth structures. It is therefore suggested that these fibers may be subserving prominent efferent roles in dental pulp not directly related to nociception.