Given the high prevalence and considerable individual and societal costs of PTSD, there are relatively few randomized, placebo-controlled trials in PTSD. Four placebo controlled trials have been performed with MAOIs, three with TCAs. Only one randomized placebo controlled trial was performed with benzodiazepines class, showing no effect of alprazolam on core PTSD symptoms. The majority of trials were done with SSRIs and novel antidepressants, the most of them showing moderate effect sizes over placebo. In past clinical trials antidepressants appeared with the best overall efficacy for the treatment of PTSD, although their effect may not be present in all symptom clusters. Although duration of majority of trials in psychiatry is conventionally set to 12 weeks, clinical trials in PTSD may require the acute phase of treatment to go beyond initial 12 weeks of treatment, especially if the trial includes more severely ill patients. Further clinical research is warranted, using new compounds, as well as those already marketed for other indications. It remains essential to investigate if certain treatments are more effective for particular symptom sets or for some subgroup of PTSD patients. Due to high placebo response and moderate effects of drugs researched in PTSD it is difficult to avoid the use of placebo in PTSD trials.