Aims This paper examines ethnic differences in licit and illicit drug use among American 8th, 10th and 12th grade students, with a particular focus on girls. Design The study uses cross-sectional data from large, ethnically diverse, nationally representative samples of 8th, 10th and 12th grade girls. Setting Data were collected through questionnaires administered in schools. Participants A total of 40 416 8th grade girls and 37 977 8th grade boys, 35 451 10th grade girls and 33 188 10th grade boys, and 33 588 12th grade girls and 31 014 12th grade boys took part in the study. Findings Across ethnic groups, drug use is highest among Native American girls and lowest among black and Asian American girls. Trend data suggest that there have been important changes in girls’ drug use over time and that girls’ and boys’ drug use patterns are converging. Conclusions Drug use is widespread among American adolescent girls. Future research should examine further girls’ drug use and seek to identify whether risk and protective factors identified in past research, based on predominantly white samples, are also important predictors for drug use among non-white girls.