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Global grain production needs a significant increase in output in the coming decades in order to cover the food and feed consumption needs of mankind. As sustainability is the key factor in production, the authors investigate global grain production, the losses along the value chain, and future solutions. Global wheat, maize, rice, and soybean production peaked at 2.102 million tons (mt) of harvested grain in 2018. Pre-harvest losses due to diseases, animal pests, weeds, and abiotic stresses and harvest destroy yearly amount to about 35% of the total possible biological product of 3.153 mt, with 1051.5 mt being lost before harvest. The losses during harvest and storage through toxin contamination are responsible for 690 mt, with a total of 1.741 mt or 83% of the total newly stored grain. Limited cooperation can be experienced between scientific research, plant breeding, plant protection, agronomy, and society, and in addition, their interdependence is badly understood. Plant breeding can help to reduce a significant part of field loss up to 300 mt (diseases, toxins, water and heat stress) and up to 220 mt during storage (toxin contamination). The direct and indirect impact of pest management on production lead to huge grain losses. The main task is to reduce grain losses during production and storage and consumption. Better harvest and storage conditions could prevent losses of 420 mt. The education of farmers by adopting the vocational school system is a key issue in the prevention of grain loss. In addition, extension services should be created to demonstrate farmers crop management in practice. A 50% reduction of grain loss and waste along the value chain seems to be achievable for the feeding 3–4 billion more people in a sustainable way without raising genetic yields of crop cultivars.