The discovery of the severe combined immunodeficiency (scid) mouse mutation has provided a tool for establishment of small animal models as hosts for the in vivo analysis of normal and malignant human pluripotent hemopoietic stem cells. Intravenous injection of irradiated scid mice with human bone marrow, cord blood, or G-CSF cytokine-mobilized peripheral blood mononuclear cells, all rich in human hemopoietic stem cell activity, results in the engraftment of a human hemopoietic system in the murine recipient. This model has been used to identify a pluripotent stem cell, termed "scid-repopulating cell" (SRC) that is more primitive than any of the hemopoietic stem cell populations identified using the currently available in vitro methodology. In this review, we describe the development and use of this model system, termed Hu-SRC-SCID, and summarize the discoveries that have resulted from the investigation of human stem cells in this model. Finally, we detail the recent extension of the original Hu-SRC-SCID model system based on the C.B-17-scid mouse as the murine host to the Hu-SRC-NOD-SCID model based on the NOD-scid mouse as the host. The engraftment of human stem cells in the Hu-SRC-NOD-SCID model is enhanced over that observed in the Hu-SRC-SCID model and results in exceptionally high levels of human hemopoietic cells in the murine recipient. Future directions to further improve the Hu-SRC-NOD-SCID model system and the potential utility of this model in the preclinical and diagnostic arenas of hematology and oncology are discussed.