The authors review both the preclinical and the clinical evidence for a role of serotonin (5-HT) systems in the regulation of drug-taking behavior. Animal studies show that pharmacologic treatments that enhance 5-HT function, notably selective reuptake inhibitors, reduce the self-administration of a variety of substances of abuse, including ethanol and cocaine. These treatments also tend to suppress consummatory behavior in general. In contrast to the broad spectrum of suppression following 5-HT enhancement, selective antagonists at the 5-HT3 receptor subtype have been reported to reduce ethanol but not cocaine or food intake. Although essentially limited to alcohol abusers, clinical studies seem to support the preclinical findings that a number of 5-HT reuptake inhibitors decrease interest in and intake of alcohol in mild-moderate ethanol-dependent individuals. Furthermore, other serotonergic drugs may show utility in the treatment of alcohol abuse. Another way in which serotonergic medications can be used in treating substance abuse is by the treatment of comorbid psychoactive illness for which such drugs are already known to be effective, e.g., depression and anxiety disorders.