Since the late 1970s, there has been remarkable growing optimism about the efficacy of drug therapy in the treatment of patients with personality disorders. But is this optimism justified? Once in a while pharmacotherapists meet personality-disordered patients who respond dramatically to a new drug after years of struggling in therapy without progress. Open-label, uncontrolled studies are fuelled by these spectacular cures. Scientific journals accept these case histories and open studies as preliminary evidence of the efficacy of a given agent and the effects that might be expected from pharmacological interventions. Subsequent reviews on the efficacy of pharmacological treatment then provide misleading overviews by suggesting that, even in the absence of placebo-controlled randomized clinical trials, these “best” results can shape an evidence-based approach.In spite of the poor evidence for the efficacy of most drugs, official “Guidelines” mimic these reviews and their conclusions and recommendations. For example, the recommendations of the American Psychiatric Association's practical guideline for the treatment of patients with borderline personality disorder (American Psychiatric Association, 2001) seem to encourage pharmacotherapy to treat symptoms during acute decompensations as well as trait vulnerability. In clinical practice, these recommendations may lead to polypharmacy that is justified by all kinds of speculative assumptions about disbalances of neurotransmitter systems (American Psychiatric Association, 2001). Unfortunately this can lead to iatrogenic neurobiological dysregulations, behavioral dyscontrol, immense side-effects, new disappointments for all parties concerned (therapists, patients, and their families) and low cost-effectiveness.