In adults, the bone marrow compartment contains hematopoietic stem cells (HSCs) which can differentiate into progenitors with more restricted lineage potential and generate all cellular elements of the blood. HSCs for stem cell transplantation can be obtained by bone marrow collection, mobilization into peripheral blood followed by apheresis, or use of stem cells from cord blood. Currently, hematopoietic stem cell transplantation (SCT) is used to treat patients with various hematological diseases. Although substantial progress has been made, a number of challenges can limit the efficacy of HSC transplantation, including the occurrence of graft-versus-host disease (GvHD) in allogeneic stem cell transplantation (ASCT), the susceptibility of patients to opportunistic infections and relapse of malignancies after SCT. Recent studies indicate that small interfering RNAs (siRNAs) can specifically and efficiently interfere with the expression of oncogenic genes. Therefore, the possibility of interfering with the expression of these proteins in hematopoietic cells may offer a new option to correct cell differentiation and function. In addition to the generation of T cells restricted by nonself MHC as reviewed by Stauss and colleagues in 1999, the modulation of NK cell receptor expression and T-cell activation is a new strategy that could limit GvHD. This chapter reviews the recent advances in ASCT and discusses the potential application of RNAi in hematopoietic cells.