This manuscript provides a comprehensive overview of bioorthogonal click-to-release (C2R) chemistry with a specific focus on its implications for biointerfaces. It surveys the major C2R reaction platforms, outlines their mechanistic principles at a conceptual level, and critically compares their reactivity–release trade-offs and biological performance. The review highlights applications in antibody-, polymer-, nanoparticle-, and hydrogel-based drug delivery, as well as in fluorogenic imaging, biosensing, and diagnostics. Emerging uses in protein activation, tissue engineering, and adaptive biomaterials are also discussed, alongside current limitations and design challenges. Overall, the manuscript positions C2R chemistry as a versatile tool for dynamic and spatially controlled manipulation of biological systems