Beta-arrestin 2 is a multifunctional key component of the G-protein coupled receptor complex and is involved in l-opiate and dopamine D2 receptor signalling, both of which are thought to mediate the rewarding effects of ethanol consumption. We identified elevated expression and of the beta-arrestin 2 gene (Arrb2) in the striatum and the hippocampus of ethanol preferring AA rats compared to their non-preferring counterpart ANA line. Differential mRNA expression was accompanied by different levels of Arrb2 protein. The elevated expression was associated with a 7-marker haplotype in complete linkage disequilibrium, which segregated fully between the lines, and was unique to the preferring line. These findings were functionally validated using mice lacking Arrb2, which displayed both reduced voluntary ethanol consumption and ethanol induced psychomotor stimulation. Our results demonstrate that beta-arrestin 2 modulates acute responses to ethanol and is an important mediator of ethanol reward.