Although the properties of nanoporous framework materials (NFMs) for high-pressure gas storage are well-known, low-level gas detection (<5 mbar) is also possible. Here, we describe a systematic investigation of NFM structure to identify advantageous features for methane sensing. Using grand canonical Monte Carlo simulations, we show that trends at low pressures relevant to sensing do not fully mirror those at high pressures. NFMs with pore diameters similar in size to methane show the highest uptake, and amine functionalization of the M 2 (dhtp) series provides modest enhancement. Unexpectedly, the presence of coordinated solvent can yield enhancements up to 250%. Our results enable prediction of NFM film thicknesses required to achieve a given methane sensitivity by three adsorption-based sensor types. Finally, the results of CH 4 /N 2 and CH 4 /H 2 O mixture simulations for promising candidate materials provide additional insight into the utility of these materials in multiple environments. Only small changes in uptake were observed when N 2 or H 2 O was introduced as a background gas, justifying the use of pure methane simulations for largescale screening of NFMs. One notable exception is Zn 2 (dhtp), which could serve well in an inert N 2 environment, but not in a humid one. Overall, these results provide general guidance for identifying effective NFMs for chemical detection, as well as for the specific case of methane, and for designing effective sensors for that purpose.