The most efficient biological catalysts often display multimetallic active sites integrating earth-abundant elements (Fe, Ni, Cu, Mo, S) that allow them to pro-mote challenging, multielectron-driven transformations with high activities. Reproducing the function of these active sites in solution models remains challenging because of the instability of these clusters outside of the enzyme scaffold. We are developing advanced, molecular and supramolecular approaches to the stabilization of biological metal-sulfur clusters for their application in challenging multielectron-driven chemistry. For example, we have demonstrated that it is possible to bind and stabilize vulnerable [4Fe–4S] clusters inside metal-organic cages that function as synthetic protein mimics. We are exploring these and other systems aimed at incorporating critical functions of the protein scaffold into a molecular model for the first time.