Global agriculture is facing one of the biggest challenges of all time. As reported by the most recent forecasts, world population is expected to reach nearly 10 billion by 2050, thus causing higher demand for food, feed, and raw materials. Wheat is among the most widely cultivated crops, also considering the great variety of their derived end-use products. Great efforts have been made so far by breeders and research institutions to increase the productivity of these important crops, but better yield still need to be reached to guarantee global food and nutrition security in the near future. Nitrogen (N) is one of the most important elements for plant growth. It is a basic constituent of several molecules such as amino acids, proteins, nucleic acids, chlorophyll, and various primary and secondary metabolites, making it essential for the cellular growth and overall plant development. In the last decades, important amounts of fertilizer, especially nitrogenous ones, have been supplied to crops to increase final yield. A big issue is represented by the actual low percentage of N taken up and utilized by plants; as a result, high concentrations of those synthetic supplements are lost in the soil and groundwaters, thus resulting in negative effects on the environment and human health. Nevertheless, the actual climate changing scenario, inducing new stresses, is a main yield-constraining factor of most cereal crops. Drought and water stress have severe and different effects on plant growth; one is represented by the restriction of nutrient uptake, which may cause a deficiency of nutrient, especially nitrogen. One possible solution to prevent further environmental issues and still guarantee the necessary food supply may be the development of more efficient crops in terms of nitrogen-use efficiency (NUE). Thus, less nitrogen would be required as supplement and at the same time, more efficient plants could make the most out of lower inputs. In this report, we will focus on the genomics of nitrogen-use efficiency in durum wheat, with a particular attention to the candidate genes which have been so far proved to be involved in NUE uptake, assimilation, and remobilization, as well as the relationship with important agronomic traits such as grain protein content.