Alcohol as well as other substances of abuse are reinforcing substances which manifest their effects through activation of the mesolimbic dopaminergic reward pathways of the brain. In animal genetic models of alcoholism, reduced dopamine levels and D2 dopamine receptor (DRD2) numbers have been found in the brains of alcohol-preferring animals. Dopamine receptor agonists reduce alcohol consumption, whereas antagonists, in general, show the opposite effect. Moreover, quantitative trait loci studies in animals suggest the DRD2 gene and the region proximate to this locus is a chromosomal "hot spot" for alcohol-related behaviors. Human studies provide additional support for connection between alcohol dependence and CNS dopaminergic function. In endocrinological studies, using dopamine receptor agonists, reduced dopaminergic activity has been found in more severe and more genetic types of alcoholics. Brain imaging studies are similarly revealing a diminished dopaminergic tone in alcoholics. Treatment of alcoholics with dopamine receptor agonists shows reduced alcohol consumption and improvements in other outcome measures. Molecular genetic studies in humans have identified an association of the Al allele of the DRD2 gene with alcoholism. Moreover, a diminished central dopaminergic function has been found in DRD2 A1 allele subjects using pharmacological, electrophysiological and neuropsychological studies. Further, treatment of alcoholics with a dopamine receptor agonist showed more salutary effects on alcoholics who carry than those who do not carry the DRD2 A1 allele. The A1 allele has also been associated with substance use disorders other than alcoholism, including and cocaine and nicotine dependence and polysubstance abuse. The emerging evidence suggests that the DRD2 is a reinforcement or reward gene. It could represent one of the most prominent single-gene determinants of susceptibility to severe substance abuse. However, the environment and other genes, when combined, still play the larger role.