The COVID-19 pandemic sparked widespread implementation of wastewater surveillance in communities across the United States to help track the spread of the disease. In contrast to clinical laboratory testing that tracks individual cases of infection, wastewater surveillance provides a way to measure the amount of DNA from pathogens coming from homes, businesses, and other institutions that share a sewer system. To help coordinate and centralize early efforts, the U.S. Centers for Disease Control and Prevention (CDC) launched the National Wastewater Surveillance System (NWSS) in September 2020, with pilot sites in eight states. As of April 2024, the NWSS is receiving data from more than 1,300 active sampling sites, covering a population of 130 million individuals. A Phase 1 report released in early 2023 examined the usefulness of the NWSS during the COVID-19 pandemic, described the potential value of a robust national wastewater surveillance system beyond COVID-19, and provided recommendations to increase the public health impact of such a system. This Phase 2 report details the technical constraints and opportunities to improve wastewater surveillance for the prevention and control of infectious diseases in the U.S. It recommends improvements in the consistency and quality of national wastewater sampling, testing, and data analysis, and identifies research and technology development needs for a national wastewater surveillance system that can serve ongoing and changing public health needs in the United States.