G-protein activated inwardly rectifying potassium (GIRK, Kir3) channel is one of the effectors in signal pathways from ethanol, opioid, dopamine, and other addictive substances. We found associations between genetic polymorphisms in the GIRK subunit genes and sensitivity to addictive substances in mice and humans. We found that fluoxetine and paroxetine, selective serotonin reuptake inhibitors (SSRIs), but not fluvoxamine, another SSRI, inhibited GIRK channels in vitro and reduced preference for methamphetamine in mice. In addition, we found that ifenprodil, a widely used drug for dizziness, also inhibited GIRK channels in vitro. Another research group has shown that ifenprodil reduced preference for addictive substances using rodents. Furthermore, we found that relapse rate and relapse risk scores were lower in alcoholics who were treated with GIRK inhibitors. We also demonstrated an inhibitory effect of ifenprodil on alcohol use in patients with alcohol dependence in a prospective, randomized, controlled, rater-blinded study. These results suggest that GIRK channels are important molecules in the reward system and candidate targets for pharmacotherapy of drug dependence.