The majority of psychopharmacological research on personality disorders has focused on borderline personality disorder (BPD). Clinical trials for schizotypal personality disorder (SPD) have been complicated by comorbidity, particularly with other personality disorders. Evidence-based pharmacotherapy for antisocial personality disorder (AsPD) is restricted to treatment of impulsive aggression. BPD patients often demonstrate high comorbidity and make numerous suicide attempts and parasuicidal gestures, conferring significantly higher risk for completed suicide. The dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower than schizophrenia. Evidence-based treatment for Avoidant personality disorder (AvPD) would include venlafaxine and selective serotonin reuptake inhibitors (SSRIs) as first-line agents. A potential caveat is mentioned for sertraline if symptoms began in childhood or adolescence, in which case lesser efficacy was reported. By understanding the neurobiology underlying increasingly complex behavior, pharmacotherapy can be optimized and targeted to personality dimensions previously considered susceptible only to psychotherapy.