Humanized mice are useful for studying human hematopoietic stem cells (HSCs) and their niche. In particular, clonal study of human HSC enables precise comparison of in vivo behavior between murine and human HSCs. A single HSC is able to reconstitute hematopoiesis even after serial transplantations in mice. While the life span of somatic cells is over that of individual in mice, this is not the case in humans. Clonal studies of human HSCs clearly demonstrated their aging in hosts. Since murine studies have demonstrated that HSCs are protected from aging by their niche in bone marrow, the humanizing niche model will reveal the precise mechanism by which human HSCs are protected from exhaustion in vivo. Direct transplantation of human mesenchymal stem cells into mouse bone marrow results in reconstitution of the functional human hematopoietic microenvironment comprised of pericytes, myofibroblasts, reticular cells, osteocytes in bone, bone-lining osteoblasts, and endothelial cells. These humanized mouse models are essential for testing whether the insights on hematopoiesis from mouse studies are applicable to humans before clinical application.