Post-traumatic stress disorder is an anxiety disorder that may occur after the individual is exposed to severe psychologic trauma such as combat, sexual assault, or childhood physical or sexual abuse. Chronic post-traumatic stress disorder may result in considerable psychologic pain and suffering for the individual in addition to significant functional impairment. In addition to the heterogeneity of symptoms that occur in post-traumatic stress disorder, there may also be extensive comorbidity with other anxiety disorders, mood disorders, psychotic disorders, and other psychiatric disorders. This complicates the treatment picture. Currently, accepted treatments for post-traumatic stress disorder include psychotherapy, in particular cognitive behavioral-based approaches and antidepressant medication. However, many patients are refractory to these initial treatments or have only a partial response. In light of this, may clinicians combine additional classes of psychotropic agents and different psychotherapeutic approaches to enhance treatment response. This article reviews the literature on the use of atypical antipsychotics in the treatment of post-traumatic stress disorder. Most of the research to date has involved combat veterans partially responsive or refractory to treatment, namely with antidepressants. Studies have shown improvement across post-traumatic stress disorder symptom clusters, as well as improvement in comorbid psychotic symptoms or disorders. More research is needed to confirm these recent findings and further delineate the role of atypical antipsychotics in the treatment of post-traumatic stress disorder. Currently, possible indications for their use include treatment-resistant post-traumatic stress disorder and post-traumatic stress disorder with comorbid psychotic features.