BACKGROUND Posttraumatic stress disorder (PTSD) is a prevalent, chronic and disabling anxiety disorder that may develop following exposure to a traumatic event. There is currently no effective pharmacotherapy for PTSD and therefore the discovery of novel, evidence-based treatments is particularly important. This review of potential novel treatments could act as a catalyst for further drug investigation. METHODS In this review, the authors discuss the heterogeneity of PTSD and why this provides a challenge for discovering effective treatments for this disorder. By searching for the neurobiological systems that are disrupted in individuals with PTSD and their correlation with different symptoms, the authors propose potential pharmacological treatments that could target these symptoms. They discuss drugs such as nabilone, d-cycloserine, nor-BNI, 7,8-dihydroxyflavone and oxytocin (OT) to target systems such as cannabinoids, glutamate, opioids, brain-derived neurotrophic factor and the OT receptor, respectively. While not conclusive, the authors believe that these brain systems include promising targets for drug discovery. Finally, the authors review animal studies, proof-of-concept studies and case studies that support our proposed treatments. CONCLUSIONS A mechanism-based approach utilizing techniques such as in vivo neuroimaging will allow for the determination of treatments. Due to the heterogeneity of the PTSD phenotype, focusing on symptomology rather than a categorical diagnosis will allow for more personalized treatment. Furthermore, there appears to be a promise in drugs as cognitive enhancers, the use of drug cocktails and novel compounds that target specific pathways linked to the etiology of PTSD.