The intersection of epidemiology and medical science forms the basis of a public health approach to challenging health issues. Although initial conceptions of epidemiology predominantly focused on infectious diseases, the epidemiological approach has been applied successfully to non-infectious or non communicable diseases including those health issues that are related to substance use. However, unlike an infectious disease or even a chronic condition such as cancer, substance use is more dynamic with changing forms of the external agent—psychoactive substances-- and the variety of sources for these ‘agents’ that may vary geographically (within and across communities), as well as sociologically (involving a variety of social groups across time and space). As such, the dynamic nature of substance use warrants an epidemiologically-informed system for its prevention and treatment that includes on-going monitoring and dynamic and timely surveillance systems that are designed to identify emerging patterns of use that have implications for prevention and treatment such as new ways to administer substances (e.g., injecting crack cocaine), new ‘mixtures’ of substances (e.g., changing the composition of substances such as mixing fentanyl with heroin or Adderall), new types of substances, and new user groups. This paper demonstrates how this type of epidemiologic information can inform the structure and function of a national comprehensive substance use service delivery system to address the issue on a population level.