Increasing demand for nutritious, safe, and healthy food because of a growing population, and the pledge to maintain biodiversity and other resources, pose a major challenge to agriculture that is already threatened by a changing climate. Diverse and healthy diets, largely based on plant-derived food, may reduce diet-related illnesses. Investments in plant sciences will be necessary to design diverse cropping systems balancing productivity, sustainability, and nutritional quality. Cultivar diversity and nutritional quality are crucial. We call for better cooperation between food and medical scientists, food sector industries, breeders, and farmers to develop diversified and nutritious cultivars that reduce soil degradation and dependence on external inputs, such as fertilizers and pesticides, and to increase adaptation to climate change and resistance to emerging pests. Intensive industrial agriculture does not appear to be sustainable and does not contribute to a healthy human diet. Reduced consumption of livestock products and increased use of plant products are central to reducing food carbon footprints and healthy eating. Fundamental to better health is understanding gene–nutrient interactions in growth and development and in disease prevention; genomics and phenomics may assist selecting for nutritionally enhanced, resource use-efficient, and stress-resilient cultivars. A paradigm shift is occurring from the current production/productivity goals to developing nutritionally enhanced and resource use-efficient crops. There is growing notion that not all healthy diets are sustainable and not all sustainable diets are healthy, thus an integral system approach will be necessary to produce sufficient, safe, and nutritionally enhanced food.