We examined the extent to which Hispanic orientation and American orientation are associated with substance use (cigarette, alcohol, and marijuana) both directly and indirectly through acculturative stress and self-esteem. Participants were 347 Hispanic early adolescents (50.7% male; mean age = 12.57, SD = 0.92, range 11-15) from two middle schools in western Michigan. Findings showed that self-esteem emerged as the most consistent predictor of likelihood and extent of substance use. Ethnic identity was positively related to risk for substance use, and acculturative stress and self-esteem mediated the relationships of Hispanic cultural orientation to alcohol use. Self-esteem was the most important protective factor against substance use, and as such, we conclude that prevention programs designed to address precocious substance use that incorporate a self-esteem building component could prove useful among Hispanic early adolescents residing in monocultural contexts within the United States.