The established immunodeficient animal models could be used as valuable resource for mechanism research of related disease in humans, drug discovery and development, translational research and stem cell research. However, it is difficult and low-efficient to establish the genetic modified animal models using traditional technologies. The reports for immunodeficient animal models are few in middle-size and large animals. Recently, several effective gene-targeting tools, including ZFNs, TALENs, CRISPR/Cas9, develop quickly and provide technology basis for the establishment of immunodeficient animal models. In this paper, the technology principles and research progresses of ZFNs, TALENs, CRISPR/Cas9 are introduced. The significant progresses of these emerging technologies achieved in immunodeficient animal models are also elaborated, including KO Rag/1 Rag2 rabbit, KO Rag/1 Rag2 pig, KO IL2rg pig, KO Ppar-γ/ Rag1 monkey, and so on. In addition to being models for researching SCID-related diseases in humans, and evaluating the efficacy and safety of stem-cell engraftment, these models may be also useful to develop surgical procedures for placement of grafts before clinical trials in humans, to produce humanized animals and bridge the gap between laboratory animal and medicical research. The immunodeficient animal models described here represent a step toward the comprehensive evaluation of preclinical cellular regenerative strategies.