Purpose of Review <p>Many people who use tobacco are affected by mental illness, and vice versa. This review summarizes leading theories for the high comorbidity of tobacco use and mental illness and emphasizes recent evidence supporting a shared genetic liability.</p> Recent Findings <p>Tobacco use and psychiatric disorders are highly heritable and genetically correlated, indicating the presence of shared genetic risk factors. Large genome-wide association studies have identified shared risk loci, some of which map to genes encoding nicotinic acetylcholine receptors and components of the dopaminergic and glutamatergic signaling pathways. The role of human genetics research in ascertaining causal relationships and in improving drug discovery efforts is also discussed. Finally, several examples of current and future lines of inquiry in the field are presented.</p> Summary <p>Genetic factors play an important role in psychiatric disorders with notable overlap in genetic risk between disorders. Further characterization of this shared genetic risk in tobacco use and mental illness will provide etiologic insights into their comorbidity and may reveal novel treatment strategies.</p>