This paper presents a comparative analysis of the prevalence of stressful life events and of the relationships between stressful life events and alcohol, illicit drug, and cigarette use among a multi-ethnic community sample (N = 2,446) clearly adolescent boys. The data were derived from a longitudinal study of substance use behaviors and their psychosocial correlates among Hispanic, African-American, and White non-Hispanic adolescent boys residing in Dade County, Florida. Similar levels of event exposure were found among the subgroups, with one exception. African Americans were significantly more likely to experience a death-related event in the past year. Stressful life events were not significantly related with substance use among African-American students. Among Hispanics and White non-Hispanics, however, a number of significant positive relationships were found. A number of bidirectional events (i.e., those events that could be either an antecedent to and/or the result of substance use) were significantly related with stressful events, highlighting the importance of longitudinal research in delineating the temporal ordering or events and outcomes. The authors conclude that future stress research with adolescents should pay particular attention to the important moderating influences of culture and ethnicity as well as to the bidirectional nature of life events and substance use.