Sequence of drug use was examined in a secondary analysis of two samples of serious drug users: one of 152 men and one of 133 women. The proportions of drug users following specified patterns of drug use onset were compared to proportions obtained in previous research in samples of high school youth, and serious drug users. The serious drug users were substantially different from high school samples in their progression of drug use. The serious drug users were less likely to follow the typical sequence identified in previous studies (alcohol, then marijuana, followed by other illicit drugs). They were more likely to have used marijuana before using alcohol, and more likely to have used other illicit drugs before using marijuana. We also found that atypical sequencing was associated with earlier initiation of the use of illicit drugs other than marijuana and greater lifetime drug involvement. These findings suggest that for a large number of serious drug users, marijuana does not play the role of a 'gateway drug'. We conclude that prevention efforts which focus on alcohol and marijuana may be of limited effectiveness for youth who are at risk for serious drug abuse.