Obsessive-compulsive disorder is a prevalent and disabling lifespan disorder. Clomipramine and the SSRIs have been found to be effective across the range of symptoms, both in acute and longer-term studies. Meta-analyses have reported a larger treatment effect for clomipramine relative to the SSRIs, but this is not supported by evidence from head-to-head comparator studies and, based on their superior safety and tolerability, SSRIs are the preferred option for long-term treatment in most cases. The treatment-effect is usually gradual and partial, and many patients fail to respond adequately to first-line treatment. Pharmacological options for refractory cases include switching SRI, increasing the dose, or augmenting with an antipsychotic agent. Novel strategies are under investigation for this highly morbid group. This paper reviews the key questions related to OCD pharmacotherapy, synthesizing evidence derived from randomized controlled trials, meta-analyses and consensus guidelines.