Gene expression analyses, gene targeting experiments and retroviral overexpression studies in the murine bone marrow transplantation model have provided strong correlative evidence for the involvement of clustered Hox genes in normal hematopoiesis. The data strongly support the hypothesis that the role of Hox genes in normal hematopoiesis is primarily at the level of hematopoietic stem cell function. A large body of evidence now links Hox genes to leukemic transformation including dysregulated HOX expression in leukemic patient samples, their involvement as oncogenic fusion proteins with NUP98 and their requirement for the oncogenicity of Mll fusions. In recent years, much attention has been devoted to the identification and characterization of leukemic stem cells. Given the documented role of Hox genes in hematopoiesis and leukemogenesis, we propose that Hox-dependent pathways are closely linked to the self-renewal program crucial to the origin and function of leukemic stem cells.