One of the goals in research in the clinical neuroscience of trauma-related disorders is to apply findings related to the effects of traumatic stress in the brain on animals and patients with trauma and stressor-related disorders, e.g. PTSD. The paradigm of translational neuroscience has been an avenue that has contributed much to a model of the neural circuitry of PTSD that is currently used in studies. In general, the neural circuits and systems mediating symptoms of all PTSD, trauma and stressor-related disorders can be studied by registering en assessing behavioral and biochemical responses to environmental/pharmacological challenge to specific neurochemical systems measuring neurotransmitters and hormone levels in blood, urine, and saliva; measuring key brain structures with neuroimaging (Magnetic Resonance Imaging, MRI); provoking disease-specific symptoms in conjunction with (functional) neuroimaging (functional MRI, fMRI), or using imaging (Positron Emission Tomography, PET) to measure neuroreceptors. The findings of the studies (research designs, methodologies, and some of the techniques) will be discussed in this chapter varying to a great extent. Three key mechanisms seen in PTSD are: stress sensitization, fear conditioning and failure of extinction. This chapter further focuses on the functional neuroimaging research conducted in PTSD. It covers various techniques (SPECT, PET and fMRI) that are used in different kinds of paradigms (resting, active tasks and stimulus presentation) and provides a global overview of the brain circuits that currently are used to explain the phenomenology in PTSD. The disorder showed remarkable heterogeneity in some recent studies. These give consideration to speculate on two models for the disorder that can alternate and coexist together. These two models will be presented, one, in which the amygdala is hyperactive, in line with fear circuitry, being the most common and dominant situation. In another model the amygdala is hypoactive, in line with predominance of symptoms of derealisation and depersonalization symptoms that are accompanying the other PTSD symptoms. Finally, the need for longitudinal studies is emphasized. Studies that assess patients before as well as after treatment are the paradigm that will be new and promising.