The article by Philip E. Dawson and Stephen B. H. Kent discusses the synthesis of native proteins using chemical ligation of unprotected peptide segments in aqueous solution. This method has become the most practical approach for the total synthesis of native proteins, enabling the elucidation of gene function, the discovery of novel biology, and the determination of three-dimensional protein structures. The authors highlight the advantages of chemical protein synthesis, including the ability to systematically tune protein properties and the development of enhanced therapeutic agents. They review the historical progress in synthetic peptide chemistry, the challenges and limitations of classical solution synthetic methods, and the introduction of solid-phase peptide synthesis (SPPS). The article also details the development of chemical ligation methods, including native chemical ligation, which allows for the site-specific ligation of unprotected peptide segments without the formation of unnatural structures at the ligation site. The authors discuss the broad scope of native chemical ligation for protein synthesis, including the successful preparation of over 300 biologically active proteins from various families. They emphasize the efficiency and accuracy of in vitro folding of synthetic polypeptide chains to form fully functional protein molecules. The article further explores the applications of chemical protein synthesis, such as the introduction of non-coded amino acids, precise covalent modifications, site-specific labeling, backbone engineering, and the development of potent therapeutic agents. Finally, the authors highlight the importance of chemical protein synthesis in rapid access to functional gene products and its utility in structural biology, particularly in NMR and X-ray crystallography studies.The article by Philip E. Dawson and Stephen B. H. Kent discusses the synthesis of native proteins using chemical ligation of unprotected peptide segments in aqueous solution. This method has become the most practical approach for the total synthesis of native proteins, enabling the elucidation of gene function, the discovery of novel biology, and the determination of three-dimensional protein structures. The authors highlight the advantages of chemical protein synthesis, including the ability to systematically tune protein properties and the development of enhanced therapeutic agents. They review the historical progress in synthetic peptide chemistry, the challenges and limitations of classical solution synthetic methods, and the introduction of solid-phase peptide synthesis (SPPS). The article also details the development of chemical ligation methods, including native chemical ligation, which allows for the site-specific ligation of unprotected peptide segments without the formation of unnatural structures at the ligation site. The authors discuss the broad scope of native chemical ligation for protein synthesis, including the successful preparation of over 300 biologically active proteins from various families. They emphasize the efficiency and accuracy of in vitro folding of synthetic polypeptide chains to form fully functional protein molecules. The article further explores the applications of chemical protein synthesis, such as the introduction of non-coded amino acids, precise covalent modifications, site-specific labeling, backbone engineering, and the development of potent therapeutic agents. Finally, the authors highlight the importance of chemical protein synthesis in rapid access to functional gene products and its utility in structural biology, particularly in NMR and X-ray crystallography studies.