A large segment of the population suffers from addiction to alcohol, smoking, or illicit drugs. Not only do substance abuse and addiction pose a threat to health, but the consequences of addiction also impose a social and economic burden on families, communities, and nations. Genome-wide linkage and association studies have been used for addiction research with varying degrees of success. The most well-established genetic factors associated with alcohol dependence are in the genes encoding alcohol dehydrogenase (ADH), which oxidizes alcohol to acetaldehyde, and aldehyde dehydrogenase (ALDH2), which oxidizes acetaldehyde to acetate. Recently emerging genetic studies have linked variants in the genes encoding the α3, α5, and β4 nicotinic acetylcholine receptor subunits to smoking risk. However, the influence of these well-established genetic variants accounts for only a small portion of the heritability of alcohol and nicotine addiction, and it is likely that there are both common and rare risk variants yet to be identified. Newly developed DNA sequencing technologies could potentially advance the detection of rare variants with a larger impact on addiction risk.