Although the treatment of patients with OCD represented one of the greatest psychopharmacologic achievements at the end of the old millennium, it should be noted that, as is almost the rule for other psychiatric disorders, one-third of the patients do not respond to the common medications used, such as SSRIs or clomipramine. This means that these drugs are effective on symptoms (or dimensions) but cannot treat the basic disorders. Obviously, this gap is related to our meager knowledge of the causal mechanisms, so that our possibilities of intervention remain limited to the pathophysiological levels but, in spite of this, are quite successful. Even though the current bulk of evidence implicating serotonin in the pathophysiology of OCD is increasing at a level and with a convergence not found in any other psychiatric disorder, it is unlikely that serotonin represents the whole story. Different studies suggest abnormalities in other neurotransmitters (such as dopamine and norepinephrine), in neuropeptides (in particular oxytocin), and in other mechanisms (such as infections and disorders of the immune system), or in second messengers that need to be elucidated. It can be hypothesized that the heterogeneity in pathophysiological mechanisms might underlie the different clinical pictures. Obviously, a better definition of these mechanisms would lead to more focused therapeutic tailoring beyond the serotonin paradigm. Moreover, the latest developments in the pharmacology of SSRIs have shown that, although they share the common property of serotonin reuptake blockade, apart from citalopram and escitalopram. they do interact with other receptors and systems and are more heterogenous than previously assumed. A few observations have, in fact, proposed that sertraline and citalopram may be still quite effective in patients with OCD resistant to other SSRIs. In any case, further controlled studies are needed to elucidate the possible different clinical responses or specificity on target symptoms of the SSRIs. OCD requires treatment for a long time; current guidelines suggest that 2 months is the minimum time to evaluate the clinical response. For this reason, short-term clinical trials, even those controlled with placebo, must be interpreted with caution. In addition, with long-term treatment, the nature and level of side effects are important to secure the patient's compliance and, therefore, to the likelihood of a successful outcome. If SSRIs in short-term use are better tolerated than clomipramine, they produce invalidating effects in long-term use, such as those involving sexual functions. This, coupled with the results of some meta-analyises suggesting that clomipramine may be more effective not only in resistant patients, raises the issue a thorough re-evaluation of their effectiveness in OCD.