Phosphorus (P) is one of the essential nutrients for plants and indispensable for plant growth and development. P deficiency severely limits crop yield and regular fertilizer applications are required to obtain high yields and prevent soil degradation. To access P from the soil, plants have evolved high and low affinity Pi transporters and the ability to induce root architectural changes to forage P. Also, adjustments of numerous cellular processes are triggered by the P starvation response, a tightly regulated process in plants. With the increasing demand for food due to the growing population, demand for P fertilizer is steadily increasing. Given the high costs of fertilizers and in light of the fact that phosphate rock, the source of P fertilizer, is a finite natural resource, there is a need to enhance P fertilizer use efficiency in agricultural systems and develop plants with enhanced Pi uptake and internal P-use efficiency (PUE). In this review we will provide an overview of ongoing relevant research and highlight different approaches towards developing crops with enhanced PUE. In this context, we will summarize our current understanding of root responses to low phosphorus conditions and emphasize the importance of combining PUE with tolerance of other stresses, such as aluminum toxicity. Of the many genes associated with Pi deficiency, this review will focus on those that hold promise or are already at an advanced stage of testing (OsPSTOL1, AVP1, PHO1, OsPHT1;6). Finally, an update is provided on the progress made exploring alternative technologies, such as phosphite fertilizer.