The lack of natural water supplies in the Middle East and North Africa region is fundamentally a crucial constraint on socioeconomic growth, development, and stability. This is the most water-scarce region in the world. The present chapter provides insights into the problem and evaluates the drivers of this challenge and the multi impacts on the regional water scarcity. It also discusses the current use and future trends in water resources, including water-quality issues. It explores selected mitigation measures with potentially high applicability in the region. These measures include a range of sustainable water productions such as desalination, treated wastewater reuse, rainwater harvesting, and artificial aquifer recharge. Case studies of shared river basins, groundwater from the region, and its associated challenges and opportunities were also presented.