Water-soluble macrocycles are useful molecular hosts for drug delivery, stimuli-responsive materials, water purification and many other applications. However, controlling the host-guest chemistry of macrocycles such as cyclodextrins under physiologically relevant conditions is a major challenge. Here we demonstrate the use of dynamic pericyclic chemistry to derivatise guests for cyclodextrins under mild conditions, thereby turning off molecular recognition. We show that the Diels-Alder [4 + 2] cycloaddition reaction between anthracene derivatives and activated alkenes proceed rapidly, selectively and reversibly in water under ambient conditions. This reaction can be used to modulate binding of both native and modified β-cyclodextrins to the anthracene. By appropriate choice of conditions, the resulting chemical reaction network could also operate under non-equilibrium steady state conditions. Finally, alkene scavengers could induce the retro-Diels Alder reactions, allowing the use of the pericyclic reaction system as a molecular switch. (Figure presented.)