In 2001, environmental chemists at the US Office of Research and Development in the Environmental Protection Agency proposed the use of a “nonintrusive tool to heighten public awareness of societal use of illicit-abused drugs and their potential for ecological consequences.” Wastewater-based epidemiology (WBE) has since become an important adjunct to established drug monitoring tools, promising cleaner and more accurate evidence. This paper focuses on the ontopolitical dimensions of WBE and its evidencing in times of global change. Using critical genealogical methods and documentary analysis, I trace the accretion of WBE as a technology of global drug surveillance, attending to how WBE has come to configure the problem of drugs as not only a problem of human health or clandestine markets, but as an ecological concern. Tracing developments through the World Drug Report and transnational surveillance systems, the genealogy examines how WBE translates from environmental science to drug policy, and back again, and how drugs and harm are problematised in these moves. The analysis identifies how WBE works to multiply complexities, relocating harm and demanding renewed attention to the biotic dimensions of drugs as they entangle in different environments. This has implications for how we measure and account for harm in drug policy, shifting attention to how drugs, human bodies, animal bodies, and their environments, as well as regimes of drug surveillance, come together. The case of WBE illuminates the challenges of evidencing drugs, and the need for approaches that focus on ecological, sociological and political configurations of drugs and harm.