The importance of increasing crop production while reducing resource inputs and land-use change cannot be overstated especially in light of climate change and a human population growth projected to reach nine billion this century. Mutualistic plant–microbe interactions offer a novel approach to enhance agricultural productivity while reducing environmental costs. In concert with other novel agronomic technologies and management, plant-microbial mutualisms could help increase crop production and reduce yield losses by improving resistance and/or resilience to edaphic, biologic, and climatic variability from both bottom-up and top-down perspectives.