Living systems choreograph molecular events with precise control of place, =me, and dynamic range to generate the spa=otemporal regula=on essen=al to life. Efforts to interrogate or modulate these processes need synthe=c (bio)chemical tools that can recapitulate their performance: an=bodies that exclusively recognize an intended epitope, drugs that precisely engage their targets, chemical transforma=ons that proceed with excep=onal selec=vity. In this light, a primary task of bioorthogonal chemistry has been to assemble a toolkit of reac=ons that proceed rapidly and selec=vely amidst the full complexity of the biological milieu . Success in this task has already enabled diverse applica=ons in chemical biology and biomedical research, with further development ongoing . Ac=ve agendas include chemical diversity and con=nuing efforts to refine the balance of reac=vity and molecular stability. Given its excep=onal reac=on kine=cs and architectural adaptability, the inverse electron demand Diels-Alder (IEDDA) reac=on between 1,2,4,5tetrazines (Tz) and trans-cyclooctenes (TCO) stands out as a bioorthogonal tool of choice for applica=ons with cri=cal =me and/or concentra=on constraints, especially for chemistry conducted in living systems .