The global need for food is posing a serious threat to water security. Treated wastewater can be used as an alternative water supply to mitigate our reliance on nonrenewable waters (defined as water that cannot be replenished within our life span). However, concerns related to emerging contaminants such as antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) can impede efforts to push for widespread use of treated wastewater in agricultural irrigation. This chapter aims to provide a better understanding of the potential concerns by first using case studies in two countries that have already practiced water reuse. Second, we collate and analyze data that suggests that wastewater treatment plants able to achieve at least 8-log reduction in microbiological contaminants may suffice as appropriate intervention barriers for ARB dissemination to the environment. This chapter also recognizes that extracellular DNA-carrying ARGs may not be effectively removed even with membrane-based treatment. There is therefore a need to assess whether extracellular DNA may accumulate in agricultural soils due to repeated use of treated wastewater and to determine the concentrations of extracellular DNA needed to significantly increase horizontal gene transfer (HGT) in the natural environment. Given the large knowledge gaps that hinder an accurate assessment of the associated risks, it would be prudent to adopt the precautionary principle and to implement appropriate intervention strategies and best management practices that minimize the impacts and concerns arising from the reuse of treated wastewater in agriculture.