Caspase-8 constructs featuring an N-terminal FGG sequence allow for selective twofold recognition by cucurbituril, which leads to an increase of the enzymatic activity in a cucurbituril dose-dependent manner. This supramolecular switching has enabled for the first time the study of the same caspase-8 in its two extreme states; as full monomer and as cucurbituril induced dimer. A mutated, fully monomeric caspase-8 (D384A), which is enzymatically inactive towards its natural substrate caspase-3, could be fully reactivated upon addition of cucurbituril. In its monomeric state caspase-8 (D384A) still processes a small synthetic substrate, but not the natural caspase-3 substrate, highlighting the close interplay between protein dimerization and active site rearrangement for substrate selectivity. The ability to switch the caspase-8 activity by a supramolecular system thus provides a flexible approach to studying the activity of a protein at different oligomerization states.