This paper explores the relationships among neighborhood disadvantage, stress, and the likelihood of drug use in a sample of adults (N = 1,101). Using the 1995 Detroit Area Study in conjunction with tract-level data from the 1990 census, we find a positive relationship between neighborhood disadvantage and drug use, and this relationship remains statistically significant net of controls for individual-level socioeconomic status. Neighborhood disadvantage is moderately associated with drug related behaviors, indirectly through increased social stressors and higher levels of psychological distress among residents of disadvantaged neighborhoods. A residual effect of neighborhood disadvantage remains, net of a large number of socially relevant controls. Finally, results from interactive models suggest that the relationship between neighborhood disadvantage and drug use is most pronounced among individuals with lower incomes.