Wastewater is becoming an important alternative resource to reduce water footprints in many sectors. The agricultural irrigation sector accounts for approximately 70% use of freshwater worldwide. Due to the volumes involved, wastewater utilization is crucial for attaining long-term sustainability of water resources since it contains many nutrients, but it also raises environmental and public health concerns, especially in the wake of the water-energy-food (WEF) nexus. It is necessary to include water quality within the water dimension of the WEF nexus to address complex and multi-disciplinary challenges facing humanity. The aim of this paper is to present the status of wastewater reuse practices in irrigation across many nations and critically discuss the challenges of the presence of pathogens, antibiotics, antibiotic-resistant bacteria and heavy metals in such treated wastewaters. Our recent studies involving detailed metagenomics of treated sewage from different sewage treatment plants of Jaipur, India, working on a range of technologies like Moving bed biofilm reactors and constructed wetlands, have indicated the presence of certain opportunistic pathogens present even in the tertiary treated sewage having extreme resistance to most antibiotics. More importantly, many of these have exhibited exceptionally high chlorine and UV resistant also, indicating high associated risk on using such waters. The use of hybrid disinfection strategy for wastewater disinfection and constructed wetlands as a polishing system may be used to minimize this risk effectively, paving way for the safe reuse of this precious misplaced resource and conserving human and environmental health.