© Springer Science+Business Media, LLC 2012. Following intravenous infusion of hematopoietic stem/progenitor cells (HSPCs) during hematopoietic cell transplantation (HCT), HSPCs home to and engraft in marrow niche microenvironment, which ultimately leads to reconstitution of whole immunological and hematological repertoire of the recipient. The homing and engraftment of HSPCs occur relatively early (during the initial stage of HCT), but have major impacts on the success and outcomes of transplantation. HSPC homing and engraftment require well-coordinated interplay involving various cells (endothelial cells, osteoblasts, osteoclasts, and other mesenchymal stem cells), cytokines and chemokines, soluble and membrane-bound factors, as well as extracellular matrix. Many aspects and the detailed mechanisms regulating HSPC homing and engraftment still remain to be elucidated. In this chapter, we first provide a brief overview of HSPC homing and engraftment processes and the interactions between HSPCs and various cell types and different molecules in the niche microenvironment. We then summarize several strategies to enhance HSPC homing and engraftment during HCT. In particular, we present ongoing studies in our laboratories using CXCR4 antagonists to enhance donor cell engraftment following HCT.