Within this landscape, the emergence of biocompa=ble bond-cleavage has expanded our func=onal range to allow selec=ve disassembly of molecules. Among the set of mechanis=cally diverse bond-cleavage reac=ons the most significant progress has been made with the Tz-triggered cleavage of TCOs (Fig. ), enabling the release of amines abached through a carbamate moiety in the allylic posi=on of the TCO . This click-to-release reac=on has found wide use in diverse applica=ons (Fig. ): cleaving ligand-TCO-drug conjugates or ac=va=ng TCO-caged prodrugs through in vivo reac=ons with intravenously administered Tz agents , or a locally injected Tz depot , an approach currently being tested in clinical trials . In parallel to drug delivery, several research groups have explored the power of these tools for ON/OFF control of (bio)molecules, including various enzymes and immunologic circuits . In contrast to these turn-on strategies, the cleavage of TCO-linked imaging agents has enabled turn-off applica=ons, including the spa=otemporal mul=plexed imaging of living cells and =ssues and the enhanced radioimaging of mAb in mice . Although these developments highlight the poten=al of Tz-triggered TCO-cleavage to interrogate biological events and drive both diagnos=c and therapeu=c strategies, major challenges in molecular design remain. Achieving op=mal performance in the in vivo context calls for a complex ensemble of interlocking proper=es: (i) excep=onal reac=on kine=cs of both the click and the release step; (ii) complete click-triggered release; (iii) extended biological stability; and (iv) modifiable reagent scaffolds that provide abachment points for diverse molecular cargo. As no exis=ng tools can achieve this full suite of characteris=cs, it remains a key challenge in the field and a topic of ac=ve problem-solving .