Bioorthogonal chemistry has revolutionized the field of chemical biology by offering unparalleled precision in initiating and controlling molecular transformations within complex biological matrices. Among the most impactful of these methods is the inverse electron demand Diels-Alder (IEDDA)-initiated reaction between 1,2,4,5-tetrazines (Tz) and trans-cyclooctenes (TCO, Fig. ). Due to its exceptional reaction kinetics, Tz/TCO click chemistry facilitates fast and efficient ligation even at minimal reactant concentrations, making it indispensable for timesensitive in vivo applications. Over the last decade, the scope of bioorthogonal chemistry has broadened significantly to encompass not only ligation reactions but also innovative strategies for bond-cleavage. This concept has seen substantial development, providing reactions to trigger the controlled release and activation of therapeutics in targeted locations. Bioorthogonal bond-cleavage initiated by Tz/TCO click reaction was pioneered by Robillard et al., who demonstrated the release of amines linked to the TCO via a carbamate functionality in allylic position (Fig. ). This click-to-release approach has been used to cleave ligand-TCO-drug conjugates or activate TCO-caged prodrugs by in vivo reaction with systemically administered or locally restricted Tz, respectively. As these methods advanced toward clinical application, the scope of Tz/TCO bond-cleavage has steadily expanded, enabling a growing number of applications in chemical biology and medicinal chemistry. Pretargeting the Tz, for instance, to organelles or solid tumors enabled targeted cleavage of TCO-conjugates. The design of caged dihydrotetrazines as light-or enzymeresponsive Tz precursors facilitates additional control of the clickto-release process. In contrast to turn-on approaches such as the release and activation of therapeutics, click-triggered cleavage of TCO-linked imaging probes has led to the concept of bioorthogonal turn-off. Based on this strategy, we developed an unprecedented method to achieve spatiotemporal multiplexed imaging of living cells and tissues via 'bioorthogonal cycling' of rapidly cleavable antibody-TCO-fluorophore conjugates. Similarly, Robillard et al. designed a radiolabeled antibody that can be cleaved upon tumor-targeting by in vivo reaction with a Tz resulting in an increased tumor-to-blood ratio due to fast excretion of the released radionuclide. While these approaches further exemplify the utility of Tz/TCO click-to-release for the development of diagnostic and therapeutic strategies, the reaction is yet limited by an unsolved trade-off between the click reactivity and release efficiency of Tz (Fig. ). In contrast to bis-alkyl-or alkyl-aryl-substituted Tz (commonly used to achieve Tz/TCO bond-cleavage), highly reactive aryl-Hor bis-pyridyl-Tz (frequently used scaffolds for rapid bioorthogonal ligation) give only poor release. A complex array of interlocking obstacles impedes access to highly performant tools.