ABSTRACT Nearly 1 million individuals have died from drug overdoses over the past two decades with the most recent mortality surges associated with opioids, namely fentanyl. Surveillance programs are critical to understanding community drug trends, yet traditional methods (e.g. surveys) are not designed to inform on such trends as they are emerging. Wastewater-based epidemiology (WBE) is an innovative approach that can identify community drug use patterns as they change and shift in near real-time, data that is critical to developing effective public health responses. Community-level drug trends have been successfully generated from wastewater for substances of current concern (e.g., fentanyl); however, implementation of WBE as a holistic framework that contributes reliable, consistent, and trusted data to stakeholders is urgently needed. Several notable gaps within this framework include the need for advanced wastewater sampling strategies, rapid and accurate identification of emergent and/or novel drugs, and integration of wastewater traditional surveillance data. Therefore, the overall objective of this proposal is to enhance the utility of WBE as an early warning system to effectively drive public health measures in impacted communities. This will be accomplished through two comprehensive specific aims that include: (1) the generation of optimal sampling regimes by considering time, granularity, frequency and the detection of new psychoactive substances as they emerge, (2) harmonization of WBE and existing epidemiologic data for analysis, interpretation, and timely dissemination through customized visualization tools. This research will be an extension of a recently completed pilot study of wastewater surveillance of fentanyl in four United States cities. Comprised of a diverse team of researchers and community partners, GatorWATCHTM has secured the required multidisciplinary expertise that has already shown success. Furthermore, integration with the National Drug Early Warning System (NDEWS) Coordinating Center will afford us an expansive network for WBE expansion and dissemination of our results. Collectively, through advancing drug measurement methodology in tandem with sophisticated data harmonization will provide a blueprint for expansion and use of WBE as an integral part of public health interventions in the fight against contemporary and emerging drug use epidemics in our communities nationwide.