Regulator of G protein–signaling (RGS) proteins are a family of more than 30 intracellular proteins that negatively modulate intracellular signaling of receptors in the G protein-coupled receptor family. This family includes receptors for opioids, cannabinoids, and dopamine that mediate the acute effects of addictive drugs or behaviors and chronic effects leading to the development of addictive disease. Members of the RGS protein family, by negatively modulating receptor signaling, influence the intracellular processes that lead to addiction. In turn, addictive drugs control the expression levels of several RGS proteins. This review will consider the distribution and mechanisms of action of RGS proteins, particularly the R4 and R7 families that have been implicated in the actions of addictive drugs, how knowledge of these proteins is contributing to an understanding of addictive processes, and whether specific RGS proteins could provide targets for the development of medications to manage and/or treat addiction.