Abstract：Disease resistance breeding in domestic animals is crucial for safeguarding the healthy development of the livestock industry and ensuring public health security. With the rapid advancement of high-throughput screening (HTS) technologies, the mining of disease resistance genes has entered a precision- and efficiency-oriented genomics era. This review systematically summarizes the principles and workflows involved in screening for disease resistance genes in domestic animals using core HTS technologies, including CRISPR-Cas9, RNA interference (RNAi), transcriptome analysis, protein interactomics, and epigenomics. It elaborates on the functional diversity of resistance genes identified through these techniques, classifying them into seven categories based on their mechanisms of action: Innate immune response, adaptive immune response, programmed cell death, viral adhesion and entry, intracellular trafficking, viral replication, and immune evasion. Furthermore, the article summarizes successful cases of creating novel disease-resistant materials and analyzes current challenges faced by HTS, such as off-target effects, efficiency problems, and data analysis complexity. Finally, the review prospects future directions involving interdisciplinary integration, technological optimization, and clinical translation, aiming to provide comprehensive theoretical references and technical pathways for disease resistance breeding research in domestic animals.
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