The authors investigated whether substance use and self-reported racial discrimination were associated in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Smoking status, alcohol consumption, and lifetime use of marijuana, amphetamines, and opiates were ascertained in 2000–2001, 15 years after baseline(1985–1986). Most of the 1,507 African Americans reported having experienced racial discrimination, 79.5% at year 7 and 74.6% at year 15, compared with 29.7% and 23.7% among the 1,813 Whites. Compared with African Americans experiencing no discrimination, African Americans reporting any discrimination had more education and income, while the opposite was true for Whites (all p < 0.001). African Americans experiencing racial discrimination in at least three of seven domains in both years had 1.87 (95% confidence interval (CI): 1.18, 2.96) and 2.12 (95% CI: 1.42, 3.17) higher odds of reporting current tobacco use and having any alcohol in the past year than did their counterparts experiencing no discrimination. With control for income and education, African Americans reporting discrimination in three or more domains in both years had 3.31 (95% CI: 1.90, 5.74) higher odds of using marijuana 100 or more times in their lifetime, relative to African Americans reporting no discrimination. These associations were similarly positive in Whites but not significant. Substance use may be an unhealthy coping response to perceived unfair treatment for some individuals, regardless of their race/ethnicity.