The present study tested if current drug use was related to acculturation (measured by language spoken at home), gender, or youth attitudes towards drugs in a large sample of 8th grade, predominantly Mexican American, Hispanic youth. The data were obtained via self-report survey from 2964 Hispanic youth in 108 schools. Hierarchical linear modeling (HLM) was used to test if acculturation, gender, or youth attitudes towards drugs predicted past 30-day use of alcohol, inhalant, or marijuana use and assess school-level influences. Acculturation and gender interacted with attitudes towards drugs to predict current alcohol use. Gender interacted with attitudes towards drugs to predict current alcohol and inhalant use. Having positive attitudes towards drugs was related to increased substance use for all three drug types. Hispanic eighth grade girls had significantly higher use rates than boys for both alcohol and inhalants. Additional research is needed to better understand the influence of acculturation on substance use among Hispanic youth.