The dopaminergic system, and in particular the dopamine D2 receptor, has been profoundly implicated in reward mechanisms in the meso-limbic circuitry of the brain. Dysfunction of the D2 dopamine receptors leads to aberrant substance (alcohol, drug, tobacco and food) seeking behavior. Decades of research indicate that genetics play an important role in vulnerability to severe substance seeking behavior. We propose that variants of the D2 dopamine receptor gene are important common genetic determinants in predicting compulsive disease.