The glial cell line-derived neurotrophic factor (GDNF) is a secreted protein, best known for its role in the development of the central and peripheral nervous systems and the survival of adult dopaminergic neurons. More recently, accumulating evidence suggests that GDNF plays a unique role in negatively regulating the actions of drugs of abuse. In this article, we review these data and highlight the possibility that the GDNF pathway may be a promising target for the treatment of addiction.