Various traumatic incidents related to natural disasters, physical assaults, and war context lead to the development of a chronic psychiatric condition with a specific cluster of symptoms diagnosed as PTSD. This problem is aggravating globally and imposes a socio-economic burden worldwide. The overlapping pathophysiology of PTSD with other psychiatric disorders makes it challenging to diagnose and treat appropriately. Treatment relapse with existing therapies also contributes towards the failure of patient compliance. Therefore, it is essential to understand the biology of PTSD in parallel to the recent understanding of neuroanatomy and associated signaling for its emergence. Apart from clinical development, syngeneic animal models of PTSD play a major role in understanding the pathological targets and their interventions. Further, the involvement of HPA axis, neurotransmitters along with anatomical regions of the brain has been emphasized. The recent development in the area of neuroinflammatory targets is also discussed in relation to PTSD treatment.