Freshwater is a precious resource, and shortages can lead to water stress, impacting agriculture, industry, and other sectors. Wastewater reuse is increasingly considered as an opportunity to meet the freshwater demand. Legislative frameworks are under development to support the responsible reuse of wastewater, i.e., to balance benefits and risks. In an evaluation of the proposed European regulation for water reuse, we concluded that the proposed regulation is not practically feasible, as the water provider alone is responsible for the risk assessment and management, even beyond their span of control. The required knowledge and resources are extensive. Therefore, without clear guidance for implementation, the regulation would hinder implementation of reuse programs. As a consequence, the current practice of uncontrolled, unintentional, and indirect reuse continues, including related risks and inefficiency. Therefore, we provide an outline of the interdisciplinary approach required to design and achieve safe, responsible water reuse. Responsible water reuse requires knowledge of water demand and availability, quality and health, technology, and governance for the various types of application. Through this paper we want to provide a starting point for an interdisciplinary agenda to compile and generate knowledge (databases), approaches, guidelines, case examples, codes of practice, and legislation to help bring responsible water reuse into practice.