Drug addiction is a brain disease with complex genetic, psychological and social factors. The dopaminergic system of the brain plays a central role in natural reward and motivation and is the main neural substrate for the actions of abusive drugs. The analysis of mice with mutations in their dopamine receptor genes has provided new information regarding the influence of individual dopamine receptors on drug actions. The use of genetic manipulation of dopamine receptors, and related intracellular signaling molecules, in mice will help to enhance our understanding of the molecular and cellular mechanisms underlying compulsive drug-seeking and drug-taking behaviors, reasons for relapse into drug addiction and persistent neuronal changes in response to repeated drug use. These studies will provide new insights for improved therapeutic strategies for the prevention and treatment of drug addiction.