Substance use theory and practice have traditionally focused on individuals who misuse substances or who are at risk for substance misuse, but this emphasis is shifting. The present study views both substance use and misuse systematically, assessing the relationships between the physical and social environments and substance use and misuse in dynamic interplay. This substance use system was examined through a survey of approximately 10,000 persons, aged 22-44, from primarily inner-city neighborhoods in the United States. Individual indicators such as race, sex, age, socioeconomic status, education, and religious service attendance relate to both the physical and interpersonal environments, even when each is controlled for the others. Qualities of both environments are strongly associated with substance dependency, even after individual indicators are controlled. These findings suggest the difficulty of bringing about change in drug and alcohol use without fundamental change in the environments where use takes place.