Irrigation with treated wastewater (TWW) and application of biosolids introduce numerous pharmaceutical and personal care products (PPCPs) into agro-food systems. While the use of TWW and biosolids has many societal benefits, introduction of PPCPs in production agriculture poses potential food safety and human health risks. A comprehensive risk assessment and management scheme of PPCPs in agro-food systems is limited by multiple factors, not least the sheer number of investigated compounds and their diverse structures. Here we follow the fate of PPCPs in the water-soil-produce continuum by considering processes and variables that influence PPCP transfer and accumulation. By analyzing the steps in the soil-plant-human diet nexus, we propose a tiered framework as a path forward to prioritize PPCPs that could have a high potential for plant accumulation and thus pose greatest risk. This article examines research progress to date and current research challenges, highlighting the potential value of leveraging existing knowledge from decades of research on other chemicals such as pesticides. A process-driven scheme is outlined to derive a short list that may be used to refocus our future research efforts on PPCPs and other analogous emerging contaminants in agro-food systems. © 2019 American Chemical Society.