SALL4, a member of the SALL gene family, is one of the most important transcriptional regulators of stem cells. It is of particular interest to stem cell biologists because it is linked to the self-renewal of both embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs), and it is involved in human leukemia. In ESCs, the Sall4/Oct4/Nanog core transcriptional network governs the self-renewal and pluripotent properties of human and murine ESCs. In normal HSCs and leukemic stem cells (LSCs), SALL4 is linked to three known pathways that are involved in self-renewal: Wnt/β-catenin, Bmi-1, and Pten. Despite the important shared role of SALL4 in self-renewal of HSCs and LSCs, our recent studies obtained through correlating global downstream target genes and unique functional studies in normal versus leukemic cells have demonstrated that SALL4 has differential effects on both pro- and anti-apoptotic pathways in normal and leukemic cells. Targeting SALL4, particularly when combined with the use of ABT-737, a BCL2 antagonist, could lead to leukemic cell-specific apoptosis. This review summarizes our current knowledge on the SALL gene family development, particularly on the role of SALL4 in stem cells, as well as tumorigenesis, especially leukemogenesis.