The mechanisms underlying predisposition to alcohol abuse and alcoholism are poorly understood. In this study, we evaluated the role of cannabinoid (CB1) receptors in (i) voluntary alcohol consumption, and (ii) acute alcohol-induced dopamine (DA) release in the nucleus accumbens, using mice that lack the CB1 receptor gene (CB1–/–). CB1–/– mice exhibited dramatically reduced voluntary alcohol consumption, and completely lacked alcohol-induced DA release in the nucleus accumbens, as compared to wild-type mice. The gender difference, with female mice consuming significantly more alcohol than wild-type male mice, was observed in wild-type mice, whereas this gender difference was nonexistent in CB1 mutant male and female mice. There was also a significant gender difference, with the wild-type, heterozygous, and mutant females consuming significantly more liquid and food than wild-type, heterozygous and mutant males. However, the total volume of fluid consumption and food intake did not differ between wild-type, heterozygous, and mutant mice. These results strongly suggest that the CB1 receptor system plays an important role in regulating the positive reinforcing properties of alcohol.