Natural gas is considered as a promising alternative to petroleum as the next generation of primary transportation fuel owing to relatively smaller carbon footprint and lower SOx/NOx emissions and to fast developments of shale gas in recent years. Since the volumetric energy density of methane amounts to only about 1% of that of gasoline at ambient conditions, natural gas storage represents one of the key challenges for prevalent deployment of natural gas vehicles. In this work, we present a molecular thermodynamic model potentially useful for high-throughput screening of nanoporous materials for natural gas storage. We investigate methane adsorption in a large library of metal-organic frameworks (MOFs) using four versions of classical density functional theory (DFT) and calibrate the theoretical predictions with extensive simulation data for total gas uptake and delivery capacity. In combination with an extended excess entropy scaling method, the classical DFT is also used to predict the self-diffusion coefficients of the confined gas in several top-ranked MOFs. The molecular thermodynamic model has been used to identify promising MOF materials and possible variations of operation parameters to meet the Advanced Research Projects Agency-Energy (ARPA-E) target set by the U.S. Department of Energy for natural gas storage. (c) 2015 American Institute of Chemical Engineers AIChE J, 61: 3012-3021, 2015