The study by Bhatia et al. describes a method to purify primitive human hematopoietic stem cells (HSCs) capable of repopulating immune-deficient mice. The authors developed a two-step strategy involving lineage-positive cell depletion followed by fluorescence-activated cell sorting (FACS) to enrich a population of cells that can multilineage repopulate NOD/SCID recipients. These SCID-repopulating cells (SRCs) were found exclusively in the CD34+ CD38- fraction, with a frequency of 1 SRC in 617 CD34+ CD38- cells. The highly purified SRCs demonstrated extensive proliferation and differentiation in NOD/SCID mice, producing approximately 400,000 progeny 6 weeks post-transplant. Flow cytometric analysis of engrafted mice revealed both lymphoid and myeloid differentiation, as well as the retention of a significant fraction of CD34+ CD38- cells. This study provides a foundation for further research on the cellular and molecular mechanisms regulating primitive human hematopoietic cells and offers a means to maintain and expand these cells during in vitro culture.The study by Bhatia et al. describes a method to purify primitive human hematopoietic stem cells (HSCs) capable of repopulating immune-deficient mice. The authors developed a two-step strategy involving lineage-positive cell depletion followed by fluorescence-activated cell sorting (FACS) to enrich a population of cells that can multilineage repopulate NOD/SCID recipients. These SCID-repopulating cells (SRCs) were found exclusively in the CD34+ CD38- fraction, with a frequency of 1 SRC in 617 CD34+ CD38- cells. The highly purified SRCs demonstrated extensive proliferation and differentiation in NOD/SCID mice, producing approximately 400,000 progeny 6 weeks post-transplant. Flow cytometric analysis of engrafted mice revealed both lymphoid and myeloid differentiation, as well as the retention of a significant fraction of CD34+ CD38- cells. This study provides a foundation for further research on the cellular and molecular mechanisms regulating primitive human hematopoietic cells and offers a means to maintain and expand these cells during in vitro culture.