There is growing research and clinical interest in the role of brain serotonin in regulating alcohol consumption, based on two lines of evidence: negative correlations between brain serotonin levels and spontaneous alcohol consumption in rodents, and decreased alcohol intake produced by drug-induced increases in brain serotonin activity in rodents and humans. Specific blockers of neuronal serotonin uptake, such as citalopram, fluoxetine, and zimelidine, are the major drugs used in such studies. More than a dozen studies have consistently found that such specific serotonin uptake blockers reduce alcohol preference and intake in rodents, whereas nonspecific monoamine uptake blockers (e.g., amitriptyline, doxepin) do not. The effect begins within 1 hr of administration, wears off within several days of stopping drug, and often shows tolerance after 4-10 days of daily administration (the opposite time course from antidepressant action in humans). In four human, double-blind, placebo-controlled studies, citalopram (40 mg but not 20 mg daily), fluoxetine (80 mg daily), and zimelidine (200 mg more than 300 mg daily) significantly reduced alcohol intake 10-26% in social drinkers, early problem drinkers, and chronic alcoholics. The effect occurred within a few days, wore off within several days of stopping drug, and lasted throughout the 2-4 weeks of drug administration, except that in the fluoxetine study with chronic alcoholics the effect was significant only during the first week. The reduced alcohol intake was not due to sedation, antidepression, or antianxiety effects, or an aversive drug-alcohol interaction, but could be explained in part by decreased appetitive behavior (two studies found that subjects lost weight) or a conditioned (taste) aversion to alcohol promoted by serotonin (as occurs in animals). Further research is also needed to clarify the neuropharmacological mechanism of action, since the alcohol intake-reducing effects in rodents are not blocked by serotonin receptor antagonists or brain serotonin depletion. Regardless of mechanism, serotonin uptake blockers offer a potentially promising new treatment for alcoholism.