The water-gas shift (WGS) reaction is central to a spectrum of industrially important catalytic processes, ranging from the manufacture of hydrogen to the processing of biomass-derived feedstocks. Recently, oxide-supported Au catalysts have attracted attention for low-temperature WGS reactions, but the role of the Au/oxide interface in promoting this chemistry remains under debate. In this contribution, we combine periodic Density Functional Theory (DFT) calculations, detailed microkinetic modeling, and rigorous kinetic measurements to elucidate the impact of this interface on the molecular-level features of WGS chemistry of a gold nanowire supported on a MgO(100) substrate. The results demonstrate that the barrier to activate water, which is prohibitively high (similar to 2 eV) on a clean Au(111) surface, is decreased to essentially zero at the Au/MgO interface. From the DFT-calculated energetics, a dual-site microkinetic model of the Au/MgO interface is constructed. Rate and thermodynamic control analysis demonstrate both the high degree of kinetic control of COOH formation at the interface and a strong influence of competitive adsorption between CO and H. A procedure to refine the microkinetic predictions by iterative replacement of the energies of kinetically sensitive steps with a higher accuracy hybrid HSE06 prediction is introduced, and the determined effective activation barriers and reaction orders agree well with the results of detailed kinetic measurements on Au nanoparticles on MgO substrates. The results clearly show the critical role that the metal/oxide interface plays in WGS catalysis, and the approach introduced to predict kinetics at the metal/oxide interface should be applicable to a variety of catalytic processes on oxide supported metal nanoparticles. (C) 2016 Elsevier Inc. All rights reserved.