This chapter addresses a variety of challenges associated with regional water management, including the resolution of conflicts between sectors in order to resolve ‘demand versus availability’ equation and the symbiosis needed between agronomy and engineering in order to optimize the performance of irrigation networks. The chapter explores the adoption of the eco-efficiency approach as a modern management concept and indicator of sustainable water use, and presents a case study to demonstrate how the eco-efficiency approach has been applied over a large irrigation district located in Puglia region (Southern Italy). The chapter looks ahead to future research trends in this area and provides detailed suggestions for further reading on the subject.