The relationship between the intensity of response to alcohol and the future development of alcohol abuse or dependence was evaluated in 454 18- to 25-year-old drinking but not alcohol dependent subjects. This sample consisted of sons of alcohol dependent fathers and family history negative controls matched on demography as well as alcohol and substance use histories. In response to an alcohol challenge at approximately age 20, 40% of the sons of alcoholics but less than 10% of the controls demonstrated less alcohol-related changes in subjective feelings, physiological measures, and motor performance. An average of 9.3 years later, a successful follow-up of 100% of the first 223 individuals revealed that the diminished response to alcohol was a potent predictor of future alcohol abuse or dependence. Neither the family history of alcoholism nor the intensity of response to alcohol at age 20 predicted drug dependence or major psychiatric disorders during the follow-up period.