The SCID-hu mouse was designed to serve as a preclinical model for the analysis of human physiology and pathophysiology. In distinction to other immunodeficient mouse models, SCID-hu mice are made upon implantation of intact human organ systems rather than dispersed cell populations. Two constructs, the SCID-hu Thy/Liv and the SCID-hu Bone models, have been developed to reproduce the differentiation and function of human hematopoietic progenitor cells within the human thymus and bone marrow microenvironments, respectively. This review focuses on several applications of these models: definition of multilineage and lineage-restricted human hematopoietic progenitor cells and evaluation of HIV disease and its treatment.