Precise genome-editing is a powerful tool for generating specific, site-directed DNA modifications. It has evolved from early in vitro applications to a wide range of sophisticated capabilities, including in vivo applications. Despite challenges such as low efficiency, delivery difficulties, and off-target effects, precise genome-editing holds great promise for treating genetic diseases. This review explores the history, mechanisms, strategies, and applications of precise genome-editing. Key events in its development include the discovery of DNA's double-helix, the identification of restriction enzymes, the development of the Cre/loxP system, and the emergence of ZFNs, TALENs, and the CRISPR/Cas system. Recent advancements include base editors (BEs) and prime editors (PEs), which allow for precise modifications without creating DNA breaks. Current delivery systems include DNA, RNA, and RNPs. Applications of precise genome-editing include gene labeling, variant screening, molecular recording, disease modeling, and gene therapy. Despite progress, challenges remain, including the need for improved efficiency, reduced off-target effects, and better delivery methods. The future of precise genome-editing is promising, with ongoing research aimed at overcoming these challenges and expanding its applications in medicine.Precise genome-editing is a powerful tool for generating specific, site-directed DNA modifications. It has evolved from early in vitro applications to a wide range of sophisticated capabilities, including in vivo applications. Despite challenges such as low efficiency, delivery difficulties, and off-target effects, precise genome-editing holds great promise for treating genetic diseases. This review explores the history, mechanisms, strategies, and applications of precise genome-editing. Key events in its development include the discovery of DNA's double-helix, the identification of restriction enzymes, the development of the Cre/loxP system, and the emergence of ZFNs, TALENs, and the CRISPR/Cas system. Recent advancements include base editors (BEs) and prime editors (PEs), which allow for precise modifications without creating DNA breaks. Current delivery systems include DNA, RNA, and RNPs. Applications of precise genome-editing include gene labeling, variant screening, molecular recording, disease modeling, and gene therapy. Despite progress, challenges remain, including the need for improved efficiency, reduced off-target effects, and better delivery methods. The future of precise genome-editing is promising, with ongoing research aimed at overcoming these challenges and expanding its applications in medicine.