Post-traumatic stress disorder (PTSD) is one of the few DSM-IV diagnoses contingent upon a psychosocial stressor. In this context, there is an urgent need to acquire a better understanding of both the adaptive and maladaptive psychobiological responses to traumatic stress. Preclinical investigators have utilized a variety of animal models to identify the behavioral and neurobiological features of the organism's response to stress. However, given the complexity of the healthy and pathological human response to physiological and psychological stress, the extent to which the animal data is immediately transferable to human remains to be fully determined. This review draws upon preclinical and clinical literature to examine the transformation of an adaptive human stress response into a maladaptive and debilitating mental disorder. An integrative psychobiological model for PTSD is presented, linking psychological processes and behavioral patterns with current findings in neurocircuitry, neurochemistry and psychophysiology. The implications of this model for the discovery of novel pharmacological approaches to the treatment of severe psychological distress are discussed.