Obsessive-compulsive disorder (OCD) is a chronic and often incapacitating disorder that is frequently complicated by mood and additional anxiety diagnoses. Although appropriate pharmacotherapy is often of great benefit, full remission is rare. Separate multi-center, placebo-controlled trials of clomipramine, paroxetine, fluoxetine, sertraline and fluvoxamine, respectively, have established the unparalleled efficacy and safety of the serotonin reuptake inhibitors (SRIs) in the treatment of OCD. Direct comparisons of SRIs suggest similar efficacy, but reduced tolerability for clomipramine in comparison to fluoxetine, fluvoxamine, sertraline and paroxetine in patients with OCD. Although 60-80% of OCD patients will respond to SRI treatment, partial symptom reduction (mean improvement, 25-40% from baseline) remains the rule. Controlled trials of adjuvant lithium, buspirone, thyroid hormone or clonazepam added to ongoing SRI therapy have failed to demonstrate substantial further antiobsessive effects. The presence of comorbid conditions, specific OCD symptom content and various other clinical features have been investigated as potential predictors of medication response in patients with OCD, but consistent factors have not yet been identified. Clinical experience and preliminary data does suggest that a lack of response to one or more SRIs does not preclude response to another SRI. An overview of the pharmacotherapy of OCD, including first-line medication(s) and the comparative efficacy and pharmacological features of the different SRIs will be presented in this review, as well as potential strategies for OCD patients who fail to respond to conventional pharmacotherapeutic interventions.