Improving phosphorus (P) crop nutrition has emerged as a key factor toward achieving a more resilient and sustainable agriculture. P is an essential nutrient for plant development and reproduction, and phosphate (Pi)-based fertilizers represent one of the pillars that sustain food production systems. To meet the global food demand, the challenge for modern agriculture is to increase food production and improve food quality in a sustainable way by significantly optimizing Pi fertilizer use efficiency. The development of genetically improved crops with higher Pi uptake and Pi-use efficiency and higher adaptability to environments with low-Pi availability will play a crucial role toward this end. In this review, we summarize the current understanding of Pi nutrition and the regulation of Pi-starvation responses in plants, and provide new perspectives on how to harness the ample repertoire of genetic mechanisms behind these adaptive responses for crop improvement. We discuss on the potential of implementing more integrative, versatile, and effective strategies by incorporating systems biology approaches and tools such as genome editing and synthetic biology. These strategies will be invaluable for producing high-yielding crops that require reduced Pi fertilizer inputs and to develop a more sustainable global agriculture.