Recent advances in Ni-based bio-inspired catalysts obtained in the Center for Molecular Electrocatalysis, an Energy Frontier Research Center (EFRC) led by the Pacific Northwest National Laboratory, demonstrated the possibility of cleaving H2 or generating H2 heterolytically with turnover frequencies comparable or superior to those of hydrogenase enzymes. In these catalysts the transformation between H2 and protons proceeds via an interplay between proton, hydride and electron transfer steps, and involves the interaction of a dihydrogen molecule with both a Ni(II) center and pendent amine bases incorporated in six-membered rings, which function as proton relays. These catalytic platforms are well designed in that when protons are correctly positioned (endo) toward the metal center, catalysis proceeds at very high rates. We show here that the proton removal from the molecular catalysts (for H2 oxidation) and proton delivery to the molecular catalysts (for H2 production) are often the rate-determining steps. Furthermore, the presence of multiple protonation sites gives rise to reaction intermediates with protons incorrectly positioned (exo relative to the metal center). These isomers are kinetically easily accessible and are detrimental to catalysis because the isomerization processes necessary to convert them to the catalytically competent endo isomers are slow. In this chapter we give an overview of the major findings of our computational investigation of proton relays for H2 chemistryand provide guidelines for the design of catalysts with enhanced activity.