Upscaling the spatial and temporal changes of carbon stocks and fluxes from sites to regions is challenging owing to the spatial and temporal variances and covariance of driving variables and the uncertainties in both the model and the input data. Although various modeling approaches have been developed to facilitate the upscaling process, few deal with error transfer from model input to output, and error propagation in time and space. The author has developed the General Ensemble Biogeochemical Modelling System (GEMS) for upscaling carbon stocks and fluxes from sites to regions with measures of uncertainty. This chapter describes the GEMS model, its application to regional- and larger-scale areas, and the new results that demonstrate the challenges of upscaling. GEMS relies on site-scale biogeochemical models to simulate carbon dynamics at the site scale. The spatial deployment of the site-scale model in GEMS is based on the spatial and temporal joint frequency distribution of major driving variables (e.g., land cover and land use change, climate, soils, disturbances, and management). At the site scale, GEMS uses stochastic ensemble simulations to incorporate input uncertainty to quantify uncertainty transfer from input to output, and to identify trends in both input data and simulation results. It permits one to simulate the range of possible permutations of input values and identify the trends and variance in both the input data and results. Using data assimilation techniques, GEMS simulations can be constrained by field and satellite observations, including estimates of net primary production (NPP) from the Moderate Resolution Imaging Spectroradiometer (MODIS), grain yield and cropping practices, and forest inventories. The modeling philosophy embedded in GEMS makes it ideal for assimilating information with various uncertainties to support estimating the spatial details of carbon sequestration potential as well as dynamic monitoring of the performance of carbon sequestration activities over large areas. As a case study, GEMS is applied to simulate the spatial and temporal details of carbon sources, sinks, and uncertainty in the Ridge and Valley ecoregion in the eastern United States