Recently there has been increased interest in the regulatory interactions between osteoblasts and cells in the surrounding bone marrow microenvironment. The proximity of hematopoietic stem cells (HSCs) with osteoblastic cells first suggested regulatory interactions, and recent data have highlighted the role of osteoblastic cells in providing a HSC niche. Reports have indicated that direct contact is necessary to mediate the osteoblastic effects and that these effects could be mediated through Notch activation. Notch signaling is important throughout development and also appears to play a critical role in cellular maturation and differentiation of osteoblastic cells and hematopoietic cells as disregulation can lead to bone loss and leukemias, respectively. In this review we discuss the current understanding of Notch signaling and how it functions in hematopoiesis, osteoblastic cells, and the interactions between HSC and their osteoblastic niche.