Substance abuse has been a thorny public health concern throughout human history. Manifestly, prevention and treatment are the two main strategies commonly adopted to tackle the problem of substance abuse. They are in fact cross-disciplinary, and they relate to the various domains of heredity, biology, psychology, cognitive science, family, social development and cultural structures. This special issue, “Substance Abuse, Environment and Public Health,” has published empirical studies from different regions and countries globally to enhance the international exchange of latest views and findings on the etiology, processes and influences of substance abuse across different domains, through which a multilevel perspective is considered more helpful for analyzing its complex nature, courses and consequences. This in turn suggests the possible need to employ multiple responses dynamically and integratively in the prevention and treatment of substance abuse.