Preservation of the mechanosensory function of osteocytes by inhibiting their apoptosis might contribute to the beneficial effects of bisphosphonates in bone. We report herein a mechanism by which connexin43 hemichannel opening by bisphosphonates triggers the activation of the kinases Src and ERK.S and promotes cell survival. Bisphosphonate-induced anti-apoptosis requires connexin channel integrity, but not gap junctions. Osteocytic cells express functional hemichannels that are opened by bisphosphonates, as demonstrated by dye uptake, regulation by established agonists and antagonists, and cell surface biotinylation. The anti-apoptotic effect of bisphosphonates depends on connexin43 expression in mouse embryonic fibroblasts and osteoblastic cells. Transfection of connexin43, but not other connexins, into connexin43 naive cells confers de novo responsiveness to the drugs. The signal transducing property of connexin43 requires the pore-forming, as well as the C-terminal domains of the protein, the interaction of connexin43 with Src, and the activation of both Src and ERK kinases. These studies establish a role for connexin43 hemichannels in bisphosphonate action, and a novel function of connexin43—beyond gap junction communication—in the regulation of survival signaling pathways.