The oxygen-evolving complex of photosystem II and the binuclear [NiFe]/[FeFe] centers of hydrogenases perform a highly efficient water splitting reaction with a mechanism yet to be established. Synthetic compounds mimicking the structures/functions of these systems show a wide range of activities, which are still far from optimal. We focus on defining electronic and geometric structural factors that determine the reactivity of proton reduction and water oxidation catalysts. The factors discovered will be utilized to optimize synthetic catalysts and extended to elucidate the mechanisms of OEC and hydrogenases.