Post-traumatic stress disorder is a difficult to treat, yet common disorder, which is associated with significant morbidity, mortality and societal burden. Comprehensive management of post-traumatic stress disorder must include both psychotherapeutic and pharmacologic components. The current evidence-based pharmacologic management approaches to post-traumatic stress disorder, suggests that first-line treatments for monotherapy are the selective serotonin reuptake inhibitors, sertraline, paroxetine and fluoxetine. Other potential options include other monotherapies including venlafaxine, mirtazapine, tricyclic antidepressants, monoamine oxidase inhibitors, as well as adjunctive usage of atypical antipsychotics, lamotrigine, trazadone and a number of adrenergic agents. A trial of therapy should be at least 8 weeks and continue for at the very least 12 months, but is likely to be much longer. In light of the risks of untreated post-traumatic stress disorder (e.g., suicide and impaired psychosocial functioning), therapy may need to be continued for 2 years or more. Pharmacologic therapy instituted at the time of acute psychologic trauma shows promise for the prevention of post-traumatic stress disorder in the future and warrants further study.