Never before has the ability to rapidly detect and characterize any pathogen, be it known or novel, been so important to protecting global health. Pathogen agnostic tools, such as next-generation sequencing (NGS), enhance global biological defense and public health by addressing this exact need, but they must be deployed in a proactive manner to reach their full benefit. Using pathogen agnostic tools only during an outbreak is too retroactive and does not allow time for containment, particularly of a novel pathogen. In this commentary, we propose the development of national guidelines for a proactive, pathogen agnostic wastewater surveillance system in the United States with a focus on localities identified for risk of zoonoses and international ports of entry.