The article reviews the progress, promise, and challenges in the development of humanized mice for studying the immune system. Humanized mice are immunodeficient mice that have been engrafted with human primary hematopoietic cells and tissues, allowing the study of human immune biology, development, and functions in vivo. Recent advances include the development of new mouse strains, such as NOD.Cg-PrkdcscidIl2rgtm1Wjl (NSG), NOD.cg-PrkdcscidIl2rgtm1Sug (NOG), and C:129S4-Rag2tm1Lefv (BRG), which support higher levels of human hematopoietic stem cell (HSC) engraftment and T cell development. Technological approaches, such as transgenic expression of human growth factors and targeted inactivation of mouse genes, have improved the function of the human immune system in humanized mice. The article also discusses the use of humanized mice in studying human infectious diseases, autoimmune diseases, and cancer immunology. Despite these advancements, challenges remain, including the limited development of lymph nodes and the need for further genetic modifications to enhance human immunity and reduce mouse innate immunity.The article reviews the progress, promise, and challenges in the development of humanized mice for studying the immune system. Humanized mice are immunodeficient mice that have been engrafted with human primary hematopoietic cells and tissues, allowing the study of human immune biology, development, and functions in vivo. Recent advances include the development of new mouse strains, such as NOD.Cg-PrkdcscidIl2rgtm1Wjl (NSG), NOD.cg-PrkdcscidIl2rgtm1Sug (NOG), and C:129S4-Rag2tm1Lefv (BRG), which support higher levels of human hematopoietic stem cell (HSC) engraftment and T cell development. Technological approaches, such as transgenic expression of human growth factors and targeted inactivation of mouse genes, have improved the function of the human immune system in humanized mice. The article also discusses the use of humanized mice in studying human infectious diseases, autoimmune diseases, and cancer immunology. Despite these advancements, challenges remain, including the limited development of lymph nodes and the need for further genetic modifications to enhance human immunity and reduce mouse innate immunity.