In this study, we found that (i) sensory nerves expressing CGRP are enriched in the periosteum of mice with bone metastasis; (ii) cancer patients with bone metastatic disease have elevated CGRP serum levels; (iii) tumor samples from patients with bone metastases express higher levels of a CGRP receptor, calcitonin receptor-like receptor (CRLR); (iv) CGRP induces proliferation of cancer cells through the CRLR/p38/HSP27 pathway; and (v) blocking CGRP, derived from sensory nerves, by monoclonal antibody against CGRP can reduce bone metastatic progression in vivo. This evidence concerns the gene CALCRL and bone metastasis.