Substance abuse disorders have a strong genetic component. Genetic risk factors associated with alcohol abuse include common variants in genes coding for alcohol-metabolizing enzymes and gamma-aminobutyric acid A receptors. Functional missense mutations in ADH1B and ALDH2 are protective against alcohol dependence. Nicotine use disorders are associated with polymorphisms in a cluster of nicotinic acetylcholine receptors on chromosome 15q24, and mutations that reduce the enzymatic activity of CYP2A6. Genetic risk factors for other illicit drug use have not been well-studied. Most genetic vulnerability toward substance use disorders remains unexplained. Future research will benefit from advanced whole-genome sequencing technologies.