Feeding the growing human population sustainably amidst climate change is one of the most important challenges in the 21st century. Current practices often lead to the overuse of agronomic inputs, such as synthetic fertilizers and water, resulting in environmental contamination and diminishing returns on crop productivity. The complexity of agricultural systems, involving plant-environment interactions and human management, presents significant scientific and technical challenges for developing sustainable practices. Addressing these challenges necessitates transdisciplinary research, involving intense collaboration among fields such as plant science, engineering, computer science, and social sciences. Five case studies are presented here demonstrating successful transdisciplinary approaches toward more sustainable water and fertilizer use. These case studies span multiple scales. By leveraging whole-plant signaling, reporter plants can transform our understanding of plant communication and enable efficient application of water and fertilizers. The use of new fertilizer technologies could increase the availability of phosphorus in the soil. To accelerate advancements in breeding new cultivars, robotic technologies for high-throughput plant screening in different environments at a population scale are discussed. At the ecosystem scale, phosphorus recovery from aquatic systems and methods to minimize phosphorus leaching are described. Finally, as agricultural outputs affect all people, integration of stakeholder perspectives and needs into research is outlined. These case studies highlight how transdisciplinary research and cross-training among biologists, engineers, and social scientists bring diverse expertise to tackling grand challenges in sustainable agriculture, driving discovery and innovation.