OBJECTIVE Among Finnish adolescent twins, we compared (a) a model that describes a direct impact of liability to tobacco use on cannabis and other illicit drug use with (b) a model that included a shared underlying liability for these substances. Furthermore, the extent to which genetic and environmental influences contribute to the covariation between liabilities to use these substances was examined. METHODS Tobacco and illicit drug use were assessed at age 17.5 years. Twin data on 3,744 individuals were analyzed using standard biometrical methods. Two alternative multivariate models were fi t and compared with Mx, a statistical program for genetic model fitting. RESULTS The multivariate model, including a direct impact of the initiation of tobacco use on illicit drug use, provided the best fit to the data. In this model, the total variation in the initiation of illicit drugs was decomposed to genetic factors (32%), common environmental factors (20%), unique environmental factors (8%), and a component due to initiation of smoking (40%). Most variation in the progression of illicit drug use was the result of initiation of smoking and illicit drug use (83%). CONCLUSIONS Liability to initiate smoking directly affects illicit drug use in our best-fitting model. Our findings suggest that several common genetic influences may be related to tobacco use and illicit drugs but that a search for specific genes underlying illicit drug use is justifi ed as well. Such specific genes may hold a key to understanding biological vulnerabilities that lead to illicit drug use, which could aid in the development of targeted interventions.