With the increase in population and the increase in demand for food, increasing the yield of crops is one of the biggest challenges facing mankind. More production of crops requires more use of fertilizers and pesticides, which leads to increased production costs, reduction of soil quality toward acidity and salinity, environmental damage by leaching of nutrients and accumulation in surface water and changing the ecosystem, as well as pollution of the air. Therefore, increasing the production of crops in the limited resources of land currently used for agriculture requires innovative methods to produce a healthier crop for human consumption and safer for the environment on the one hand, and on the other hand, by reducing water and energy consumption and cost. Many transcription factors and regulatory gene networks collaborate during nutritional deprivation to uphold nutrient homeostasis. Enhancing the Nutrient Use Efficiency (NUE) is crucial for achieving sustainable output with improved quality. This review presents prospective targets appropriate for genome editing to improve our understanding and the performance of NUE. The various techniques for utilizing essential negative and positive regulators in genome editing are also explained. Potential targets for genome editing are negative regulators of nutrient signaling, which can enhance nutrient absorption and stress signaling in resource-limited settings. The CRISPR/dCas9 method provides an additional benefit by utilizing transcriptional activators and repressors to increase the expression of specific genes of interest selectively. Utilizing CRISPR/Cas technology to generate nutrient-efficient plants would accelerate the genetic enhancement of crop tolerance to nutrient stress and promote the sustainability of agricultures.