The purpose of this study was to identify cultural, social, and intrapersonal factors associated with tobacco, alcohol, and illicit drug use among students attending dropout prevention/recovery high schools. Four mutually exclusive categories of substance use were used as outcome measures, and religiosity, educational achievement, educational aspiration, family caring, others caring, self-esteem, optimism, coping, depression, loneliness, and self-efficacy were used as predictor variables. In the final multivariate model more family caring and loneliness were inversely associated with marijuana use; young age, more family caring, less coping ability, church attendance, and low educational aspirations were significantly associated with cocaine use. This study demonstrates the importance of health education and health promotion programs for students attending alternative high schools which include prevention of initiation, as well as treatment.