To investigate human hematopoiesis and immunity in vivo, we have been making efforts to reconstitute these systems in mice by intravenously injecting purified human stem cells into NOD/SCID/IL2rgKO newborns. This xenogeneic transplantation system supports long-term engraftment, multi-lineage differentiation, and self-renewal capacity of human cord blood-derived hematopoietic stem cells (HSCs). We here introduce our recent application of the NOD/SCID/IL2rgKO newborn xenotransplant system to create in vivo models for human hematological malignancies and to understand pathophysiology of human AML.