Sclerostin (SOST) and Secreted Frizzled Related Protein 2 (SFRP-2) are two Wnt antagonists that are important for maintaining bone homeostasis through different modes of regulation. Wnt signaling is an important regulator of hematopoietic stem cell and progenitor cells as well as lymphoid cells, but there are only a few studies that have investigated the influence of Wnt antagonists on hematopoiesis. In addition, Wnt signaling guides osteoblastic fate, in turn directing mineralization, which can also potentially influence hematopoiesis. Wnt antagonists are currently being targeted for treatments in osteoporosis, further demonstrating the importance of understanding how Wnt antagonists influence hematopoietic cell fate decisions. In this dissertation, I have shown that mineralization using in vitro mineralizing and non-mineralizing MC3T3-E1 osteoblast like cell lines display increased SFRP-2 expression, which correlated to a decrease in hematopoietic differentiation in mineralizing MC3T3-E1 co-cultures seeded with hematopoietic stem cells. We extended this study to an in vivo system using sclerostin knockout (Sost-/-) mice that display overactive osteoblast and osteocytes populations. Sclerostin is secreted by osteocytes and mature osteoblasts transitioning to the osteocyte fate and blocks Wnt signaling by binding to Lrp4/5/6 receptors. Using Sost-/- mice, I observed decreased B cell survival in the bone marrow due to changes in the B cell microenvironment through alteration in CXCL12 and SCF. Interestingly, competitive and serial transplantation assays demonstrated that the absence of Sost resulted in increases in hematopoietic stem cell engraftment in the bone marrow. Taken together, our work demonstrates an underappreciated role of the Wnt antagonist Sclerostin, as well as the influence of osteoblast mineralization, on hematopoiesis.