On a global scale, climatic changes are widely expected to affect water resources and, therefore, the sustainable development in arid and hyper-arid regions. Thus, a full understanding of the role of groundwater in global water resources is essential for managing water deficiency in worldwide arid regions and for vastly improving water resources management for generations to come. In this context, the Nile Delta represents a typical example of the complexity of land development in a region facing water scarcity due to rapid population growth. In the Nile Delta region, groundwater quality is controlled mainly by saltwater intrusion from the north due to Sea-Level Rise (SLR) and surface contaminants from the common wastewater networks and anthropogenic activities in heterogeneous topmost clay and silt soils. Thus, the Delta faces many environmental problems and challenges now and in the future due to unplanned water resource pumping and saltwater intrusion due to SLR. The groundwater in the area is considered the second most important water resource, after the surface Nile water network. It represents a key component for any sustainable development strategy in agricultural activities and urban expansion. To elaborate on these challenges and the future development of groundwater aquifers, in-depth analyses of vulnerability conditions related to water quality and recharge systems under the impact of SLR, surface wastewater pollution, and intensive use were addressed in the present chapter. The present work aims to draft a roadmap for groundwater management in the Nile Delta. Therefore, we present the status of the main aquifer systems in the Nile Delta according to their quality, change in water salinization, and future forecasting for the aquifer characteristics. The results of multidisciplinary hydrochemical, groundwater vulnerability modeling, and hydrogeophysical investigations were discussed in-depth to assess the water quality and validate the inferred transport models of contaminants and saltwater.