Using twins assessed during adolescence (Virginia Twin Study of Adolescent Behavioral Development: 8-17 years) and followed up in early adulthood (Young Adult Follow-Up, 18-27 years), we tested 13 genetically informative models of co-occurrence, adapted for the inclusion of covariates. Models were fit, in Mx, to data at both assessments allowing for a comparison of the mechanisms that underlie the lifetime co-occurrence of cannabis and tobacco use in adolescence and early adulthood. Both cannabis and tobacco use were influenced by additive genetic (38-81%) and non-shared environmental factors with the possible role of non-shared environment in the adolescent assessment only. Causation models, where liability to use cannabis exerted a causal influence on the liability to use tobacco fit the adolescent data best, while the reverse causation model (tobacco causes cannabis) fit the early adult data best. Both causation models (cannabis to tobacco and tobacco to cannabis) and the correlated liabilities model fit data from the adolescent and young adult assessments well. Genetic correlations (0.59-0.74) were moderate. Therefore, the relationship between cannabis and tobacco use is fairly similar during adolescence and early adulthood with reciprocal influences across the two psychoactive substances. However, our study could not exclude the possibility that 'gateways' and 'reverse gateways', particularly within a genetic context, exist, such that predisposition to using one substance (cannabis or tobacco) modifies predisposition to using the other. Given the high addictive potential of nicotine and the ubiquitous nature of cannabis use, this is a public health concern worthy of considerable attention.