Wastewater treatment and reuse has passed through different development stages with time. This study reviews the most essential changes in water reclamation and reuses over millennia, focusing on initial approaches in the Hellenic world and discussing the current situation. Based on archeological evidence and time records, the awareness of the Greeks regarding land disposal, irrigation, and water reuse is highlighted. The latter has evolved into a plethora of applications, with Direct Potable Reuse (DPR) representing one of the last modern frontiers. Currently, advances in wastewater treatment and the spreading of wastewater treatment plants producing large amounts of treated effluents increase the potential for water reuse. This is regarded as a critical option for the continuing protection of water resources and human health, while concurrently satisfying water demand, particularly in areas subject to increased water scarcity. The main constraints in the expansion of water reuse practices are discussed, focusing on wastewater treatment efficiency and quality effluent standards issues, as well as on the lack of motivations related to the acceptability of this practice by final users. Against these challenges, the need for a transition from an “issue-by-issue” approach to a broader integrated water management framework is highlighted.