Eph receptors and ephrin ligands mediate cell-cell communication during development of various tissues including the nervous system, vasculature, and skeletal system. During bone remodeling in adult mice, Eph-ephrin bidirectional signaling regulates differentiation and function of bone cells such as osteoclasts and osteoblasts. When expressed in osteoclasts, ephrinB2 and ephrinA2 act as a coupling stimulator and a coupling inhibitor, respectively, thus enhancing or suppressing osteoblast differentiation. In neurons and endothelial cells, signaling downstream of Eph-ephrin interaction often controls the actin cytoskeleton and dynamic alterations in the topology of lipid bilayers associated with endocytosis, axon guidance and angiogenesis, and mediates the switch from cell attraction to repulsion through activation of multiple effectors such as Rho family small GTPases. Here we review similarities and differences between downstream events of Eph-ephrin signaling in bone cells compared to other cell types.