SALL4 is a zinc finger DNA-binding protein that has been well characterized in development and in embryonic stem cell (ESC) maintenance. Notably, SALL4 may be one of the few genes that are also involved in tissue stem cells in adults, and SALL4 protein expression has been correlated with the presence of stem and progenitor cell populations in various organ systems and also in human cancers. In normal hematopoiesis, SALL4 expression is restricted to the rare hematopoietic stem/progenitor cell (HSC/ HPC) fractions but is rapidly silenced following lineage differentiation. In hematopoietic malignancies, however, SALL4 is persistently expressed and its expression levels are linked with deteriorated disease status. Furthermore, SALL4 activation participates in the pathogenesis of tumor initiation and disease progression. This chapter summarizes recent advances in our knowledge of SALL4 biology with a focus on its regulatory functions in normal and leukemic hematopoiesis. A better understanding of SALL4's biologic functions and mechanisms is needed to facilitate the development of advanced therapies in future.