Obsessive-compulsive disorder (OCD) responds preferentially to drugs which powerfully inhibit the reuptake of serotonin at the synapse, that is, clomipramine and the selective serotonin reuptake inhibitors (SSRIs). OCD is a lifespan disorder, and effective treatment early on may prevent the problems of long-term chronicity. This chapter includes an analysis of the limited studies that have been conducted in children with OCD. There were few treatment-refractory cases and most had long histories of stable, severe, untreated illness. In addition to clomipramine's powerful serotonin reuptake inhibitor (SRI) activity, its active metabolite has strong noradrenergic properties. Treatment-resistant OCD is now receiving systematic evaluation. Evidence-based options include continuing the SSRI at maximal dose levels for a longer period, increasing the dose beyond formulary limits, or augmenting the SSRI with a first- or second-generation antipsychotic, while novel treatments such as compounds acting on serotonin or glutamate neurotransmission are under evaluation.