Due to the importance of Phosphorus (P) on plant development and reproduction, global P security has emerged as a key factor towards global food security. Together with multiple agrochemicals, P-based fertilizers have become the pillars that sustain our food production systems. Therefore, improving the genetics and biology of key crops such as maize, rice, wheat and soybean to develop varieties better adapted to thrive under environments that present low phosphate (Pi) availability and that possess higher Pi-fertilizer use efficiency is imperative. In this review, we summarize the current understanding of Pi nutrition in plants, with particular focus on crops, and provide new perspectives on how to harness the ample repertoire of genetic mechanisms behind plant low-Pi adaptive responses that can be utilized to design smart low-Pi tolerant plants. We discuss on the potential of implementing more integrative, versatile and effective strategies by incorporating genome editing and synthetic biology approaches to reduce Pi-fertilizer input and enable global food security in a more sustainable way.