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Osteocalcin (OC) is a small, acidic extracellular protein synthesized by osteoblasts during bone formation. 3 residues of gamma-carboxy glutamic acid, formed in a vitamin K dependent process, enable highly specific binding to ionic or bone mineral calcium. Some OC is released to circulation (pOC) and can serve as a biomarker of bone turnover. A series of experiments indicated that OC is stress-responsive in ways that vary with the type of stressor. Those in which the HPA axis predominates slowly decrease OC synthesis and secretion while sympathetic neural activation rapidly increases pOC. The advent of an OC null mutant mouse (KO) led to discovery of several functions for the protein outside the skeleton, most notably in regulation of energy metabolism. The KO mouse also exhibits numerous behavioral traits that are characteristic of sensory impairment. The discovery of OC protein in sensory ganglia stimulated further investigation of the interaction of sensory responses and both OC gene expression and OC protein in trigeminal and dorsal root ganglia. A recently discovered G-coupled protein receptor has been suggested as a potential OC receptor in combination with calcium ions. Because of the importance of ionic calcium to signal transduction in the nervous system, the presence of this unique calcium binding protein in neurons led to the hypothesis that OC functions as a neuropeptide. Implications of this potential new function are discussed.