Irrigation using untreated wastewater poses health risks to farmers and consumers of crop products, especially vegetables. With hardly any wastewater treatment in Ghana, a multiple-barrier approach was adopted and safe re-use practices were developed through action research involving a number of stakeholders at different levels along the food chain. This paper presents an overview of safe re-use practices including farm-based water treatment methods, water application techniques, post-harvest handling practices, and washing methods. The overview is based on a comprehensive analysis of the literature and our own specific studies, which used data from a broad range of research methods and approaches. Identifying, testing, and assessment of safe practices were done with the active participation of key actors using observations, extensive microbiological laboratory assessments, and field-based measurements. The results of our work and the work of others show that the practices developed had a great potential to reduce health risks, especially when used to complement each other at different levels of the food chain. Future challenges are the development of a comprehensive framework that best combines tested risk-reduction strategies for wide application by national stakeholders as well as their potential implementation into legally enforceable national standards