Multimetallic cofactors supported by weak-field donors frequently function as reaction centers in metalloproteins, and many of these cofactors catalyze small molecule activation (e.g., N 2 , O 2 , CO 2) with prominent roles in geochemical element cycles or detoxification. Notable examples include the iron-molybdenum cofactor of the molybdenum-dependent nitrogenases, which catalyze N 2 fixation, and the NiFe 4 S 4 cluster and the Mo(O)SCu site in various carbon monoxide dehydrogenases. The prevailing proposed reaction mechanisms for these multimetallic cofactors relies on a cooperative pathway, in which the oxidation state changes are distributed over the aggregate coupled with orbital overlap between the substrate and more than one metal ion within the cluster. Such cooperativity has also been proposed for chemical transformations at the surfaces of heterogeneous catalysts. However, the design details that afford cooperative effects and allow such reactivity to be harnessed effectively in homogeneous synthetic systems remain unclear. Relatedly, hydride donors ligated to these metal cluster cofactors are suggested as precursors to the state that reacts with substrates; here too, however, the reactivity of hydride-decorated clusters supported by weak-field ligands is underexplored.