Hox genes, first recognized for their role in embryonic development, may also play lineage-specific functions in a variety of somatic tissues including the hematopoietic system. Expression of these transcription factors has been demonstrated both in normal and leukemic human and hematopoietic cells, suggesting functional roles in hematopoietic cell growth and differentiation. Several recent studies have shown that Hox proteins are involved in controlling proliferation of primitive bone marrow cells and also in altering differentiation of myeloid as well as lymphoid progenitors, alterations that also can contribute to leukemic transformation. Hox genes, together with their upstream regulators and downstream target genes, may play key roles in fundamental processes controlling hematopoietic stem cell properties.