Depersonalization disorder (DPD) is a chronic and distressing condition with a prevalence in the general population between 0.8 and 2%. Several neurobiological studies in the last decade have shown that patients have suppressed limbic activation to emotional stimuli. Such findings are in line with a model which suggests that the condition is generated by an anxiety-triggered, 'hard-wired' inhibitory response to threat. Such a mechanism would ensure the preservation of adaptive behavior, during situations normally associated with overwhelming and potentially disorganizing anxiety. In DPD, such a response would become chronic and dysfunctional. Depersonalization remains a condition for which no definitive treatment exists, and for which conventional medications, such as antidepressants or antipsychotics, have been found to be of little value. Fortunately, a few promising lines of pharmacological treatment have emerged in recent years, although more rigorous studies are needed. For example, a number of studies suggest that opioid receptor antagonists such as naltrexone and naloxone are useful in at least a subgroup of patients. In spite of initial expectations, the use of lamotrigine as a sole medication has not been found useful. However, open-label trials suggest that its use as an add-on treatment with selective serotonin reuptake inhibitors (SSRIs) is beneficial in a substantial number of patients. Similarly, the use of clonazepam, particularly in conjunction with SSRI antidepressants, appears to be beneficial in patients with high levels of background anxiety. In line with the stress-related model of depersonalization, those neurotransmitter systems of relevance to depersonalization are known to play important inhibitory roles in the regulation of the stress response.