International agreements to limit greenhouse gas emissions require verification to ensure that they are effective and fair. Verification based on direct observation of atmospheric greenhouse gas concentrations will be necessary to demonstrate that estimated emission reductions have been actualized in the atmosphere. Here we assess the capability of ground-based observations and a high-resolution (1.3 km) mesoscale atmospheric transport model to determine a change in greenhouse gas emissions over time from a metropolitan region. We test the method with observations from a network of CO2 surface monitors in Salt Lake City. Many features of the CO2 data were simulated with excellent fidelity, although data-model mismatches occurred on hourly timescales due to inadequate simulation of shallow circulations and the precise timing of boundary-layer stratification and destratification. Using two optimization procedures, monthly regional fluxes were constrained to sufficient precision to detect an increase or decrease in emissions of approximately 15% at the 95% confidence level. We argue that integrated column measurements of the urban dome of CO2 from the ground and/or space are less sensitive than surface point measurements to the redistribution of emitted CO2 by small-scale processes and thus may allow for more precise trend detection of emissions from urban regions.