The article by John C. Jewett and Carolyn R. Bertozzi reviews the emerging field of bioorthogonal chemistry, focusing on copper-free click cycloaddition reactions. These reactions are designed to be selective and biocompatible, allowing for the formation of covalent bonds within complex biological systems without disrupting cellular processes. The review highlights the historical context of click chemistry, emphasizing the transition from academic interest to practical applications. It discusses the challenges of performing selective reactions in living systems and introduces bioorthogonal reagents, particularly those based on azides and strained alkenes. The authors detail the design and synthesis of various bioorthogonal reagents, including cyclooctynes, oxanorbornadienes, trans-cyclooctenes, tetrazines, and nitrile oxides. These reagents are synthesized through a series of chemical transformations, often involving ring strain and functional group manipulations. The review also explores the biological applications of these reagents, such as labeling biomolecules, imaging cell surfaces, and studying protein interactions. The article concludes by discussing the future directions of bioorthogonal chemistry, emphasizing the need for new reagents with improved efficiency and reduced side reactions. It highlights the potential of combining multiple bioorthogonal reactions to study complex biological interactions and the promise of photo-click chemistry for imaging applications.The article by John C. Jewett and Carolyn R. Bertozzi reviews the emerging field of bioorthogonal chemistry, focusing on copper-free click cycloaddition reactions. These reactions are designed to be selective and biocompatible, allowing for the formation of covalent bonds within complex biological systems without disrupting cellular processes. The review highlights the historical context of click chemistry, emphasizing the transition from academic interest to practical applications. It discusses the challenges of performing selective reactions in living systems and introduces bioorthogonal reagents, particularly those based on azides and strained alkenes. The authors detail the design and synthesis of various bioorthogonal reagents, including cyclooctynes, oxanorbornadienes, trans-cyclooctenes, tetrazines, and nitrile oxides. These reagents are synthesized through a series of chemical transformations, often involving ring strain and functional group manipulations. The review also explores the biological applications of these reagents, such as labeling biomolecules, imaging cell surfaces, and studying protein interactions. The article concludes by discussing the future directions of bioorthogonal chemistry, emphasizing the need for new reagents with improved efficiency and reduced side reactions. It highlights the potential of combining multiple bioorthogonal reactions to study complex biological interactions and the promise of photo-click chemistry for imaging applications.