Feeding nutrition-dense food to future world populations presents agriculture with enormous challenges as estimates indicate that crop production must as much as double. Crop production cannot be increased to meet this challenge simply by increasing land acreage or using past agricultural intensification methods. Food production doubled in the past through substantial use of synthetic fertilizer, pesticides, and irrigation, all at significant environmental cost. Future production of nutrition-dense food will require next-generation crop production systems with decreased reliance on synthetic fertilizer and pesticide. Here, we present three case studies detailing the development of cover crops and plant-beneficial microbes for sustainable, next-generation small grain, tomato, and oilseed rape production systems. Cover crops imparted weed and pathogen control and decreased soil erosion and loss of soil nitrogen, phosphorus and carbon, while plant-beneficial microbes provided disease control and phosphorus fertility. However, yield in these next-generation crop production systems at best approximated that associated with current production systems. We argue here that to substantially increase agricultural productivity, new crop germplasm needs to be developed with enhanced nutritional content and enhanced tolerance to abiotic and biotic stress. This will require using all available technologies, including intensified genetic engineering tools, in the next-generation cropping systems.