Significant advances have been made in the past 5 years in defining efficacious treatments for post-traumatic stress disorder (PTSD). Currently, sertraline is the first and only FDA-approved medication for this complex and often chronic illness. Other serotonergic antidepressants, such as paroxetine, fluoxetine and nefazodone, have well-controlled or replicated open-label evidence of efficacy. Anticonvulsants are also being studied as potential alternatives to treatment. Finally, atypical antipsychotic medications have shown promise in open-label trials. Clearly, more controlled studies are needed. This is especially true in males and in combat trauma-induced PTSD, where the effects of pharmacotherapy are less robust than in females or civilian trauma-induced PTSD. Also, there are virtually no data on pharmacotherapy for acute stress reaction or for PTSD in children. Future directions for research may focus on combination treatment in the more treatment-resistant patient populations.