The mainstay of treatment for chronic posttraumatic stress disorder (PTSD) is a combination of psychotherapy and medication treatments. The first-line medications for PTSD are antidepressants, with two selective serotonin reuptake inhibitors (sertraline and paroxetine) currently Food and Drug Administration-indicated for PTSD. However, many patients do not have an adequate response to antidepressants, therefore, combinations with other antidepressants or with other classes of psychotropic medication are often utilized to enhance the therapeutic response. Other agents that have been used include mood stabilizers, antiadrenergics, anxiolytics, and atypical antipsychotics. The heterogeneity of symptom clusters in PTSD as well as the complex psychiatric comorbidities (eg, with depression or substance abuse) further support the notion that combinations of medications may be needed. To date, there is a paucity of data to support specific strategies for augmenting antidepressants in PTSD. This review will address representative existing studies and discuss several potential pharmacologic strategies for patients suffering from treatment refractory PTSD.