Despite the serious health and economic consequences of drug and alcohol abuse and dependence, few studies have prospectively examined the etiology of this problem in non-clinical populations. This longitudinal study examines childhood and adolescent antecedents of drug and alcohol problems in adulthood among an African American cohort (n = 1242; 51% female) from Woodlawn, a neighborhood in Chicago. The participants were followed from age 6 to 32 years, and data were collected in first grade, adolescence, and adulthood. Structural equation modeling showed that, for both males and females, educational attainment was directly associated with a reduced risk for substance use problems. For males, first grade shyness was directly associated with a reduced risk of substance use problems, and adolescent substance use was directly associated with an increased risk. First grade aggression, low family socioeconomic status (SES), and low school bonds were indirectly associated with substance use problems for both males and females. For males, first grade underachievement had an indirect effect, and, for females, first grade shyness and strong parental supervision had indirect effects. This study is among the first to identify life course trajectories to substance use problems among an African American, community-based population. These results help to identify the targets and timing of interventions that may help to reduce the risk of drug and alcohol problems in adulthood.