The observa=on that tautomeriza=on to both 1,4-and 2,5-DHP accelerates at higher buffer concentra=ons or under acidic condi=ons inspired the use of direc=ng groups to influence the post-click reac=on network . Efforts thus far have exclusively focused on incorpora=ng these tautomeriza=on direc=ng groups (TDG) into the Tz scaffold, crea=ng "bioorthogonal scissors" to enhance the release of cleavable TCOs (Fig. )-a general approach that has extended from the widely used rTCO and cTCO (the first releasing linker), to C2TCO (which enables omnidirec=onal cleavage independent of click orienta=on), and more recently to bicyclic cleavable TCO linkers . The first genera=on of Tz-scissors incorporated alkyl subs=tuents func=onalized with CO2H or NH3 + moie=es that accelerate intramolecular proton transfer, enhancing tautomeriza=on and subsequent elimina=on, but at the cost of the rela=vely low click reac=vity of alkyl-subs=tuted Tz . To combine the benefits of click-accelera=ng (hetero)aryl subs=tuents with release-enhancing direc=ng groups, we and others developed Tz scissors that integrate TDGs into (hetero)aryl scaffolds. The resul=ng bis-hydroxyaryl , bis-amido-pyridyl and bis-sulfonated hydroxyaryl Tz 37 produced further gains in release efficiency, but at the cost of significant reduc=ons in both click reac=vity and stability compared to the parent Tz without The outcome of click-to-release reac6ons hinges on the tautomeriza6on steps downstream from IEDDA liga6on, with the ini6al 4,5-dihydropyridazine (4,5-DHP) tautomer siJng at a cri6cal nexus. Persistence of this tautomer, conversion to the non-releasing 2,5-DHP, and forma6on of dead-end isomers can all stand in the way of conversion to the releasing 1,4-DHP. Intramolecular direc6ng groups provide a key strategy to promote the release route, which can also be accelerated by environmental factors like buffer composi6on and low pH. (c) The performance of known cleavable TCO tools strongly depends on the Tz trigger. While general architectures that resist dead end forma6on can yield useful degrees of release, tautomeriza6on-direc6ng groups (TDG) are able to accelerate post-click tautomeriza6on and thereby enhance elimina6on. First-genera6on Tz modified with TDGs deployed alkyl subs6tuents with CO2H and NH3 + func6onali6es, while second-genera6on tools include hydroxy-pyridyl, amido-pyridyl and sulfonated hydroxyphenyl-Tz, all of which achieve efficient release at the cost of reduced click reac6vity and limited stability. (d) Equipping the TCO scaffold itself with an intramolecular direc6ng group enables complete and near-instantaneous release with all commonly applied classes of tetrazines; in contrast to omnipresent trade-offs in Tz design, this approach can achieve both excep6onal click-to-release kine6cs and remarkable stability.