The present invention demonstrates that SALL4A and SALL4B are strong positive regulators of hematopoetic stem cell expansion. HSCs receiving expression of SALL4A or SALL4B are able to achieve a high-level of expansion. Cultures of SALL4-transduced cells results in extensive HSC expansion with over 1000-fold higher levels than controls within 2 to 3 weeks and expanded HSCs show no or very little maturation. Moreover, the expansion occurs quite rapidly with significant HSC growth in just a few days. In addition, SALL4-induced HSC expansion exhibits no impairment of hematopoietic cell differentiation. SALL4 appears to function in the maintenance of an undifferentiated proliferation state and block cell differentiation for HSCs.