We have been developing “humanized mice” to study normal human hematopoiesis and immunity as well as human hematologic malignancies. When we transplanted purified human hematopoietic stem/progenitor cells, we could detect multiple human immune subsets in thymus, bone marrow, spleen, and intestinal mucosa. Therefore the in vivo system is valuable to understand how stem/progenitor cells determine their in vivo fate and to what extent human immune cells are functional in each organ. Using human immune cells and leukemic cells of humanized mice and those of human individuals, we have been taking a multi-omics approach to measure expression of biologically relevant molecules. By comparing normal and leukemic cells of human origin, we aim to find therapeutic targets that are specifically expressed by leukemic cells. Through multi-faceted analyses, we hope to create therapeutic modalities for poor prognosis leukemia and to find key molecules determining stemness in human hematopoiesis.