Recent advances have established connexin43 (Cx43) as a key regulator of osteoblast function and of bone response to mechanical stimuli. Work by independent laboratories has consistently demonstrated postnatal development of larger than normal cross-section of long bones after conditional ablation of the Cx43 gene, Gja1, selectively in osteoblasts and/or osteocytes. This phenotype is caused by excessive endocortical bone resorption associated with periosteal expansion and cortical thinning. Review of published data suggests that the earlier in the osteogenic lineage is Gja1 deleted, the more severe is the cortical phenotype, implying functional roles of Cx43 at different stages of the osteoblast differentiation program. Such cortical modeling abnormalities resemble the changes occurring in the cortex upon disuse or aging. Indeed, Cx43 deficiency desensitizes endocortical osteoclasts from activation induced by removal of mechanical load, thus preventing medullary area expansion. The action of Cx43 on cancellous bone is controversial. Furthermore, the absence of Cx43 in osteoblasts and osteocytes results in activation of periosteal bone formation at lower strains than in wild-type bones, suggesting that Cx43 deficiency increased cortical sensitivity to mechanical load. Thus, Cx43 modulates cortical bone modeling in homeostatic conditions and in response to mechanical load by restraining both endocortical bone resorption and periosteal bone formation. Cx43 may represent a novel pharmacologic target for improving cortical bone strength through modulation of mechano-responsiveness.