Few medications are effective in treating obsessive-compulsive disorder (OCD). As monotherapy, only potent serotonin (5-HT) reuptake inhibitors (SRIs) consistently exert an intrinsic therapeutic action in OCD. Their use in OCD, however, differs from their use in depression. This paper first reviews the evidence supporting the key role of 5-HT as a pivotal neurotransmitter in the anti-OCD response. Then, we describe the practicalities of SRI use, followed by the steps that can be taken when these medications do not produce an adequate clinical response. We provide specifics for the treatment of children and adolescents with OCD. We include a brief description of the brain circuitry involved in OCD and the mechanisms of action of the pharmacologic agents reported to be effective in this disorder, as well as those that are useful in depression but not in OCD. We present this information to promote better understanding of the research endeavours needed to develop new pharmacotherapeutic approaches.