The processes of bone modeling and remodeling are crucial in the skeleton's functions as a supportive and protective structure, a mineral reservoir, and an endocrine organ. The coordination between bone cell activities (bone formation and bone resorption), necessary to maintain the integrity of the skeleton during these processes, is mediated at least in part by cell–cell and cell–environment interactions across gap junctions and hemichannels. The increasing number of genetically engineered Connexin 43 (Cx43) knockout and missense mouse models have provided insight into the complex and critical roles of Cx43-containing gap junctions and hemichannels in the development and turnover of the skeleton, in differentiation, activity and survival of the bone cell lineages, and in the cellular and molecular mechanisms by which Cx43 functions and assists in mediating cellular responses to stimuli in bone. Cx43 may be an important potential therapeutic target, making it crucial that we continue to gain understanding of the multiple and complex roles of Cx43 in bone. J. Cell. Biochem. 115: 1646–1658, 2014. © 2014 Wiley Periodicals, Inc.