An understanding of potential factors controlling methane emissions from natural wetlands is important to accurately project future atmospheric methane concentrations. Here, we examine the relative contributions of climatic and environmental factors, such as precipitation, temperature, atmospheric CO2 concentration, nitrogen deposition, wetland inundation extent, and land-use and land-cover change, on changes in wetland methane emissions from preindustrial to present day (i.e., 1850–2005). We apply a mechanistic methane biogeochemical model integrated in the Community Land Model version 4.5 (CLM4.5), the land component of the Community Earth System Model. The methane model explicitly simulates methane production, oxidation, ebullition, transport through aerenchyma of plants, and aqueous and gaseous diffusion. We conduct a suite of model simulations from 1850 to 2005, with all changes in environmental factors included, and sensitivity studies isolating each factor. Globally, we estimate that preindustrial methane emissions were higher by 10% than present-day emissions from natural wetlands, with emissions changes from preindustrial to the present of +15%, −41%, and −11% for the high latitudes, temperate regions, and tropics, respectively. The most important change is due to the estimated change in wetland extent, due to the conversion of wetland areas to drylands by humans. This effect alone leads to higher preindustrial global methane fluxes by 33% relative to the present, with the largest change in temperate regions (+80%). These increases were partially offset by lower preindustrial emissions due to lower CO2 levels (10%), shifts in precipitation (7%), lower nitrogen deposition (3%), and changes in land-use and land-cover (2%). Cooler temperatures in the preindustrial regions resulted in our simulations in an increase in global methane emissions of 6% relative to present day. Much of the sensitivity to these perturbations is mediated in the model by changes in methane substrate production and the areal extent of wetlands. The detrended interannual variability of high-latitude methane emissions is explained by the variation in substrate production and wetland inundation extent, whereas the tropical emission variability is explained by both of those variables and precipitation.