Ever since the visionary publication of the Sharpless group about click chemistry, this field has grown significantly and has had a tremendous impact on drug discovery, bioconjugation and modern chemistry in general. Many click reactions are bioorthogonal, a term first used by Bertozzi in 2003, indicating that functional groups are only mutually reactive and do not interfere with biochemical processes occurring in living systems. Examples of bioorthogonal click reactions include the strain-promoted azide-alkyne cycloaddition (SPAAC), the Staudinger ligation and strain-promoted oxidation-controlled cyclooctyne-1,2quinone cycloaddition (SPOQC). In the last decade, bioorthogonal chemistry has successfully been employed in both diagnostic (e.g. radiolabeling) and therapeutic applications such as antibody-drug conjugates (ADCs) and prodrugs. The inverse-electron-demand Diels-Alder reaction (IEDDA), a reaction between an electron-rich dienophile and an electron-poor diene, has been applied for the ligation of transcyclooctenes (TCOs) and tetrazines (Tz). This bioorthogonal ligation usually shows high reaction rates and makes in vivo bioconjugation possible at low concentrations, as demonstrated in numerous studies. As a next step, in 2013 Versteegen et al. reported on the design and synthesis of TCO derivatives that upon reaction with a tetrazine eliminate a substituent at the allylic position of the TCO. This so-called click-to-release approach was applied to enable sitespecific and traceless drug release upon TCO-tetrazine ligation. The fast reaction kinetics and click and release capability of the TCO-tetrazine adduct opens up countless possibilities for novel applications in drug release and beyond. However, the complex synthesis of TCOsespecially of the releasing onesprevents the roll-out of this versatile technology towards novel applications.