Immunodeficient animal models play an important role in preclinical research and are important experimental tools in modern biomedical research that are widely used in immunology, genetics, oncology, microbiology,and other research fields. Gene editing is a technology for targeted modification of biological genomes. From emergence to application, it has greatly promoted the development of biomedical research. Gene editing technology mainly includes homing endonucleases, zinc finger nucleases, transcription activator-like effector nucleases, and the CRISPR/ Cas9 system.Researchers have used these technologies to establish various types of immunodeficient animal models, each with advantages and limitations. In recent years, a large number of studies have confirmed that the human immunodeficient animal model accurately simulates the functions of cancer cells, drugs, and the human immune system, better simulates human diseases,and is widely used to study human immunobiology and the potential mechanisms of complex diseases. In this article, we review the progress in the research and application of gene editing technology to the establishment of immunodeficient animal models, discuss in depth the problems and optimization strategies of gene editing technology in the preparation of immunodeficient animal models, and present its future development prospects to provide references for researchers to select and establish immunodeficient animal models.