Primary production is the basis of the food chain for humans and all other animal species on Earth. This study estimates the sensitivity of global terrestrial net primary production (NPP) to both past and future human modifications of the landscape in comparison with decadal-scale interannual variability in NPP. Landscape modification in the past has had spatially varying effects on NPP, generally within the range of interannual variability. In the future, landscape modification is likely to occur predominantly in the humid tropics with large NPP reductions outside the range of interannual variability. Future landscape modification, in the absence of improved land management, is likely to be a more significant negative influence on NPP than in the past, which should be considered in studies investigating the biospheric response to climate change, enhanced atmospheric carbon dioxide, nutrient deposition, and other forcing factors for NPP.