Background: Consumption of nicotine, alcohol, and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability to substance involvement. Methods: To elucidate its genetic architecture, we modeled a common liability inferred from genetic correlations among 6 measures of dependence and frequency of use of nicotine, alcohol, and cannabis. Results: Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to substance involvement, of which 67% were novel and not associated with the 6 phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine receptor D2 gene) and showed enrichment for several components of the central nervous system (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic [gamma-aminobutyric acidergic]) that are thought to modulate drug reinforcement. Genetic correlations with other traits were most prominent for reward-related behaviors (e.g., risk taking, cocaine use, and opioid use) and mood (e.g., depression, insomnia). Conclusions: These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of substance involvement and help to elucidate the genetic architecture underlying the use of common psychoactive substances.