The quantity of hydrocarbon gases trapped in natural hydrate accumulations is enormous, leading to a significant interest in the evaluation of their potential as an energy source. It has been shown that large volumes of gas can be readily produced at high rates for long times from some types of methane hydrate accumulations by means of depressurization-induced dissociation, and using conventional horizontal or vertical well configurations. However, these resources are currently assessed using simplified or reduced-scale 3D or 2D production simulations. In this study, we use the massively parallel TOUGH+HYDRATE code (pT+H) to assess the production potential of a large, deep ocean hydrate reservoir and develop strategies for effective production. The simulations model a full 3D system of over extent, examining the productivity of vertical and horizontal wells, single or multiple wells, and explore variations in reservoir properties. Systems of up to 2.5 M gridblocks, running on thousands of supercomputing nodes, are required to simulate such large systems at the highest level of detail. The simulations reveal the challenges inherent in producing from deep, relatively cold systems with extensive water-bearing channels and connectivity to large aquifers, mainly difficulty of achieving depressurization and the problem of enormous water production. Also highlighted are new frontiers in large-scale reservoir simulation of coupled flow, transport, thermodynamics, and phase behavior, including the construction of large meshes and the computational scaling of larger systems.