This review article provides a comprehensive overview of precise genome-editing platforms and their applications in human diseases. The authors trace the history of genome-editing from the discovery of DNA's double-helix structure in the 1950s to the development of modern techniques. They discuss the evolution of various genome-editing methods, including homologous recombination (HR), zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR/Cas system. The article highlights the advantages and limitations of each method, emphasizing the increasing precision and versatility of genome-editing tools. The review also covers the current state of genome-editing strategies, focusing on the delivery systems used to deploy these components, such as DNA, RNA, and ribonucleoproteins (RNPs). It discusses the challenges and limitations of HDR-mediated genome-editing, including low efficiency, off-target effects, and the requirement for double-strand breaks. The authors explore alternative strategies like non-HR-mediated genome-editing, including the Cre/loxP system, base editing, prime editing, and CRISPR-associated transposase (CAST). Finally, the article summarizes the applications of precise genome-editing in labeling endogenous genes, screening genetic variants, molecular recording, generating disease models, and gene therapy, both ex vivo and in vivo. It concludes by discussing potential future advances in the field, emphasizing the need for further research to address remaining challenges and improve the efficiency and safety of genome-editing technologies.This review article provides a comprehensive overview of precise genome-editing platforms and their applications in human diseases. The authors trace the history of genome-editing from the discovery of DNA's double-helix structure in the 1950s to the development of modern techniques. They discuss the evolution of various genome-editing methods, including homologous recombination (HR), zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR/Cas system. The article highlights the advantages and limitations of each method, emphasizing the increasing precision and versatility of genome-editing tools. The review also covers the current state of genome-editing strategies, focusing on the delivery systems used to deploy these components, such as DNA, RNA, and ribonucleoproteins (RNPs). It discusses the challenges and limitations of HDR-mediated genome-editing, including low efficiency, off-target effects, and the requirement for double-strand breaks. The authors explore alternative strategies like non-HR-mediated genome-editing, including the Cre/loxP system, base editing, prime editing, and CRISPR-associated transposase (CAST). Finally, the article summarizes the applications of precise genome-editing in labeling endogenous genes, screening genetic variants, molecular recording, generating disease models, and gene therapy, both ex vivo and in vivo. It concludes by discussing potential future advances in the field, emphasizing the need for further research to address remaining challenges and improve the efficiency and safety of genome-editing technologies.