Fast and complete click-to-release, driven by molecules with excellent in vivo stability: these are the prerequisites for actua=ng efficient bioorthogonal bond-cleavage in complex physiological environments. While a long campaign of tetrazine design has achieved stepwise progress towards this goal, here we demonstrate that moving the tautomeriza=on-driving force from the Tz to the TCO can immediately unlock next-level molecular tools. By shiUing the locus of control, release efficiency is rendered broadly independent of Tz structure, and click orienta=on becomes irrelevant, providing the new freedom to design custom tetrazines tailored for any specific applica=on. This structural flexibility makes iTCO and the kine=c gold standard Pyr2 the perfect match for click-to-release, eleva=ng bioorthogonal bond-cleavage to a performance level historically taken for granted only in liga=on.