In the present day, most people who experience a traumatic or distressing event are prone to the development of Post-Traumatic Stress Disorder (PTSD). Currently, the FDA-approved medications for this condition include selective serotonin reuptake inhibitors such as sertraline and paroxetine, in addition to antidepressants. If taken for an extended period, these medications can have negative side effects and are only effective against certain symptoms. The limited treatment options available are a result of the limited understanding of PTSD pathophysiology. In this section, we discuss the novel pathophysiology of PTSD in greater detail. This review highlights various animal models that can be employed to evaluate drugs in a translational manner for human studies. Further, this review covers the current treatment of PTSD, drugs that are being tested in clinical trials, drugs that have failed in clinical trials, and a discussion of drugs targeting new targets, such as melatonin agonists, Neurokinin-1 antagonists, neuropeptide-Y agonists, and orexinergic antagonists. Recently, antikindling medications and psychedelics have become widely discussed. Psychological interventions, such as cognitive-behavioral therapy and prolonged exposure therapy, are often prescribed as supplementary treatments or even as initial treatments due to their lack of side effects and their ability to help the individual grow emotionally and personally. Fortunately, some of the drugs are being tested in phase 4 clinical trials, such as oxytocin and suvorexant, which involve a set of symptoms; thus, comprehensive research on combined approaches could give us a better comprehension of pharmacotherapy for PTSD.