A robust animal model for “hypothesis-testing/mechanistic” research in human immunology and immuno-pathology should meet the following criteria.First,it has well-studied hemato-lymphoid organs and target cells similar to those of humans.Second,the human pathogens establish infection and lead to relevant diseases.Third,it is genetically inbred and can be manipulated via genetic,immunological and pharmacological means.Many human-tropic pathogens such as HIV-1 fail to infect murine cells due to the blocks at multiple steps of their life cycle.The mouse with a reconstituted human immune system and other human target organs is a good candidate.A number of human-mouse chimeric models with human immune cells have been developed in the past 20 years,but most with only limited success due to the selective engraftment of xeno-reactive human T cells in hu-PBL-SCID mice or the lack of significant human immune responses in the SCID-hu Thy/Liv mouse.This review summarizes the current understanding of HIV-1 immuno-pathogenesis in human patients and in SIV-infected primate models.It also reviews the recent progress in the development of humanized mouse models with a functional human immune system,especially the recent progress in the immunodeficient mice that carry a defective gammaC gene.NOD/SCID/gammaC-/(NOG or NSG) or the Rag2-/-/gammaC-/double knockout (DKO) mice,which lack NK as well as T and B cells (NTB-null mice),have been used to reconstitute a functional human immune system in central and peripheral lymphoid organs with human CD34+ HSC.These NTB-hu HSC humanized models have been used to investigate HIV-1 infection,immuno-pathogenesis and therapeutic interventions.Such models,with further improvements,will contribute to study human immunology,human-tropic pathogens as well as human stem cell biology in the tissue development and function in vivo. A robust animal model for “hypothesis-testing / mechanistic ” research in human immunology and immuno-pathology should meet the following criteria. First, it has well-studied hemato-lymphoid organs and target cells similar to those of humans. Second, the human pathogens establish infection and lead to relevant diseases. Third, it is genetically inbred and can be manipulated via genetic, immunological and pharmacological means. Many human-tropic pathogens such as HIV-1 fail to infect murine cells due to the blocks at multiple steps of their life cycle. The mouse with a reconstituted human immune system and other human target organs is a good candidate. A number of human-mouse chimeric models with human immune cells have been developed in the past 20 years, but most with only limited success due to the selective engraftment of xeno-reactive human T cells in hu-PBL-SCID mice or the lack of significant human immune responses in the SCID-hu Thy / Liv mouse. This review summarizes the current understanding of HIV-1 immuno-pathogenesis in human patients and in SIV-infected primate models. Still also reviews the recent progress in the development of humanized mouse models with a functional human immune system, especially the recent progress in the immunodeficient mice that carry a defective gammaC gene.NOD / SCID / gammaC - / (NOG or NSG) or the Rag2 - / - / gammaC- / double knockout (DKO) mice, which lack NK as well as T and B cells been used to reconstitute a functional human immune system in central and peripheral lymphoid organs with human CD34 + HSC.These NTB-hu HSC humanized models have been used to investigate HIV-1 infection, immuno-pathogenesis and therapeutic interventions.Such models, with further improvements , will contribute to study human immunology, human-tropic pathogens as well as human stem cell biology in the tissue development and function in vivo.