OCD is an anxiety disorder that was once viewed as rare and very difficult to treat. Although the first evidence that a serotonergic drug, clomipramine, might be effective in treating symptoms of OCD was published by Fernandez-Cordoba and Lopez-Ibor Alino in 1967, controlled trials demonstrating the efficacy of pharmacologic treatments in OCD did not appear until the 1980s. The availability of potentially effective treatments, combined with the awareness of prevalence rates for the disorder that are higher than previously believed, led to considerable interest in OCD. Numerous studies have been undertaken to investigate the biology of OCD. The observation that drugs that act by inhibiting serotonin uptake, such as clomipramine, fluvoxamine, sertraline, and fluoxetine, are effective in treating symptoms of OCD has resulted in intense interest in the relationship between serotonin and this disorder. Several lines of investigation support a serotonergic hypothesis for the pathophysiology and treatment of this disorder. Clomipramine, a tricyclic antidepressant that is a potent serotonin uptake inhibitor, was the first pharmacologic treatment for OCD to be studied in large multicenter trials. The successful outcome of these studies resulted in marketing approval by the United States Food and Drug Administration in 1989. Subsequently, similar multicenter trials have been undertaken with the selective serotonin uptake inhibitors fluvoxamine, sertraline, and fluoxetine. Results from these multicenter trials indicate that all these drugs are more effective than placebo in treating OCD. However, meta-analytic techniques applied to the data from controlled trials of these drugs suggest that the effect size for clomipramine is somewhat larger than that of the selective serotonin uptake inhibitors. A number of other drugs that affect serotonin through mechanisms other than uptake inhibition have been tried as treatments for OCD. Because of the small size of many of these studies, it is difficult to evaluate them in the context of the multicenter trials that studied hundreds of patients. Nevertheless, there may be a role for other serotonergic drugs in the treatment of OCD, particularly as adjunctive treatments used to enhance the effect of the serotonin uptake inhibitors. The data supporting the use of adjunctive treatment are limited and cannot be considered to demonstrate definitively the value of augmentation strategies with adjunctive treatment. Nevertheless, the serotonin uptake inhibitors, although effective in a large number of patients, do not appear to provide adequate symptom relief for some patients. Furthermore, among the patients who do respond to serotonin uptake inhibitors, complete remission in uncommon, which leaves a need for improvement of therapies.(ABSTRACT TRUNCATED AT 400 WORDS)