There are several problems with the drugs currently used to decrease alcohol consumption (i.e., alcohol-sensitizing drugs, such as disulfiram). Their efficacy is unproven, they are associated with toxicity, and there are several contraindications for use. New therapies are needed because alcohol-related problems affect almost 20% of the adult population. A new strategy was developed that involves attenuation of alcohol intake via serotonin uptake inhibitors. Since several experiments showed that serotonin uptake inhibitors consistently attenuated ethanol intake in rats, we tested their effects in humans. In four randomized, double-blind, placebo-controlled studies serotonin uptake inhibitors (zimelidine, citalopram, viqualine, and fluoxetine) decreased total number of drinks consumed by early stage problem drinkers by an average of 20-30%. However, marked interindividual variations in the pattern of response to serotonin uptake inhibitors have been observed, and we have been unable to identify subject traits or drug factors that predict pattern of response. Effects on ethanol intake are distinct from the antidepressant properties of these drugs, and they are most likely due to facilitation of satiety signals. Because of these promising and consistent results, further testing in a therapeutic context is under way. Serotonin uptake inhibitors suggest an innovative approach for moderating ethanol intake in problem drinkers.