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The rapid development of electrophilic warhead chemistry, chemical biology methods, and high\u2010throughput screening technologies has shifted covalent drug discovery from serendipitous identification to target\u2010oriented and rational design. In recent years, phage display, mRNA display, and DNA\u2010encoded library technologies have enabled the efficient de novo discovery of covalent peptides and small molecules, expanding the accessible chemical space for targeting cysteine, lysine, tyrosine, serine, and other reactive residues. Meanwhile, artificial intelligence has further accelerated covalent drug research by supporting covalent database construction, binding\u2010site prediction, virtual screening, molecular generation, and structure\u2010based ligand optimization. This article reviews recent advances in high\u2010throughput strategies for targeted covalent drug discovery, with a focus on phage display, mRNA display, DNA\u2010encoded libraries, and artificial intelligence (AI)\u2010assisted approaches. We further discuss current challenges and future opportunities in the field and provide our perspectives on emerging directions for next\u2010generation covalent ligand discovery.<\/jats:p>","DOI":"10.1002\/chem.71680","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T10:50:22Z","timestamp":1789123822000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High\u2010Throughput Technologies for Targeted Covalent Drug Discovery: Recent Advances and Perspectives"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0483-9671","authenticated-orcid":false,"given":"Haipeng","family":"Yu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Microbial Technology, Institute of Microbial Technology Shandong University  Qingdao P. R. 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