The article "Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality" by Ellen M. Sletten and Carolyn R. Bertozzi reviews the development and applications of bioorthogonal chemical reactions in studying biomolecules in their native cellular environments. Bioorthogonal reactions are crucial for selective modification of biological species in living systems, allowing researchers to probe complex cellular processes without interfering with normal biological functions. The authors provide a historical perspective on the evolution of protein bioconjugation techniques, from classic residue-specific methods to modern methods involving metal-mediated transformations and the use of unique amino acid sequences. They discuss the development of bioorthogonal transformations involving unnatural functional groups and methods to incorporate these groups into various biomolecules. The article also covers the application of bioorthogonal reactions in labeling biomolecules, including the condensation of ketones/aldehydes with amine nucleophiles, the Staudinger ligation of azides and triarylphosphines, and the reactions of azides and alkynes. The authors highlight the importance of optimizing the kinetics of these reactions for in vivo labeling studies and the challenges posed by the toxicity of certain reagents. Finally, they explore emerging bioorthogonal reactions involving alkenes and their potential applications in complex biological systems.The article "Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality" by Ellen M. Sletten and Carolyn R. Bertozzi reviews the development and applications of bioorthogonal chemical reactions in studying biomolecules in their native cellular environments. Bioorthogonal reactions are crucial for selective modification of biological species in living systems, allowing researchers to probe complex cellular processes without interfering with normal biological functions. The authors provide a historical perspective on the evolution of protein bioconjugation techniques, from classic residue-specific methods to modern methods involving metal-mediated transformations and the use of unique amino acid sequences. They discuss the development of bioorthogonal transformations involving unnatural functional groups and methods to incorporate these groups into various biomolecules. The article also covers the application of bioorthogonal reactions in labeling biomolecules, including the condensation of ketones/aldehydes with amine nucleophiles, the Staudinger ligation of azides and triarylphosphines, and the reactions of azides and alkynes. The authors highlight the importance of optimizing the kinetics of these reactions for in vivo labeling studies and the challenges posed by the toxicity of certain reagents. Finally, they explore emerging bioorthogonal reactions involving alkenes and their potential applications in complex biological systems.