Skeletal integrity is maintained through the tightly regulated bone remodeling process that occurs continuously throughout postnatal life to replace old bone and to repair skeletal damage. This is maintained primarily through complex interactions between bone resorbing osteoclasts and bone forming osteoblasts. Other elements within the bone microenvironment, including stromal, osteogenic, hematopoietic, endothelial and neural cells, also contribute to maintaining skeletal integrity. Disruption of the dynamic interactions between these diverse cellular systems can lead to poor bone health and an increased susceptibility to skeletal diseases including osteopenia, osteoporosis, osteoarthritis, osteomalacia, and major fractures. Recent reports have implicated a direct role for the Eph tyrosine kinase receptors and their ephrin ligands during bone development, homeostasis and skeletal repair. These membrane-bound molecules mediate contact-dependent signaling through both the Eph receptors, termed , and through the ephrin ligands, referred to as . This review will focus on Eph/ ephrin cross-talk as mediators of hematopoietic and stromal cell communication, and how these interactions contribute to blood/ bone marrow function and skeletal integrity during normal steady state or pathological conditions.