Background : Context processing imbues appropriate salience to the stimuli that is encountered. This ability enables us to hide from a predator in the wild, but to enjoy a visit to the zoo, although the lion may look the same in both contexts. Failures in contextual processing can lead to inappropriate fear responses rooted in failures to use safety cues, consider internal states, anticipate events, or appraise them properly. Posttraumatic stress disorder (PTSD) is associated with exaggerated fear, unwanted recollection, and inappropriate emotional and social responses. We proposed that PTSD pathophysiology involves deficits in context processing and examined this hypothesis using PTSD animal model and fMRI studies in patients with PTSD. Methods : Using validated animal model of PTSD, we examined fear conditioning, fear extinction and context-dependent extinction recall, and fear renewal in single prolonged stress (SPS)-exposed animals. We further examined the relationships between glucocorticoid receptors (GRs) upregulation in SPS, and fear renewal deficits were observed. Using 3T fMRI paradigm, we examined fear conditioning, fear extinction, extinction recall, and fear reinstatement in PTSD patients and trauma-exposed control subjects. Results : In humans, we found that fear-conditioning procedures activated fear-associated brain regions, but PTSD patients had similar fMRI activation maps to trauma-exposed controls during fear conditioning and extinction. However, they exhibited decreased responses to contextual signals of safety and danger. In animal work, we found that the SPS-exposed animals exhibited normal levels of conditioning and extinction, but specific deficits in context-dependent extinction recall and fear renewal. In “dismantling” studies, only animals exposed to full SPS and that demonstrated largest upregulation of GR in hippocampus and prefrontal cortex exhibited fear renewal deficits. Conclusions : These results demonstrate contextualization deficits in PTSD subjects. PTSD animal model findings mirror those observed in PTSD patients and further implicate specific molecular targets in defined brain regions in contextualization deficits. Together, this set of studies demonstrates the combined power of translational research into trauma psychopathology.