The literature to date that examines the biology of the acute stress reactions suggests that relatively lower baseline cortisol is associated with the development of PTSD. This is particularly informative because of the ongoing controversy surrounding baseline cortisol in PTSD. Studies have found low baseline cortisol, normal range, and elevated baseline cortisol in chronic PTSD, and it has been unclear whether this reflects methodologic differences across studies or true heterogeneity within the disorder. Thus, the few studies to date support the finding of low-normal baseline cortisol in chronic PTSD and suggest that it is a pre-existing functional trait. Whether it plays an etiologic role or is an epiphenomenon of some other process is unclear. What does seem clear, however, is that this characteristic is relatively nonspecific to PTSD, given the fact that low cortisol has been observed in multiple subject populations, including normal individuals under chronic stress as well as chronic medical conditions (for review see [23]). For example, it is possible that reduced baseline cortisol reflects the net result of input to the hypothalamus from cortical and subcortical regions of the brain linked to increased vigilance, sensitization to trauma because of prior traumatic experiences, or genetic factors. For example, primate studies have demonstrated persistent alterations in HPA axis functioning in animals reared by mothers living in moderately stressful conditions [24]. The development of PTSD is associated with sensitization of the startle response. Because the neurobiology of startle is well characterized, this finding implicates a role for specific neurocircuitry in PTSD [25]. Non-habituation of the startle response in PTSD appears related to sensitization specifically to contextual cues (i.e., the environment) that signal the presence of potential threat of danger-related fears [26]. This may be the neurobiological correlate to the over-generalization seen in PTSD that distinguishes the disorder from a simple trauma-induced phobia. The bed nucleus of the stria terminalis (BNST) is specifically implicated from preclinical research in the mediation of context-dependent cues [1]. Treatments that result in down-regulation of the BNST are therefore of particular interest in therapeutic models of prevention after trauma. The fact that a number of vulnerability factors associated with increased risk for developing PTSD are also likely to be biologically based (e.g., a genetic component, prior psychiatric history, prior family of history of psychiatric disorder), provides further evidence in support of a role for psychobiological factors in producing PTSD. Nevertheless, the considerable overlap on these measures between those who will develop PTSD, and those who eventually recover spontaneously, belies any attempt to identify any single or pathognomonic biological marker for risk. For now, the standard of care in predicting level of symptomatology and prognosis in the acute setting continues to be based on careful, informed, serial assessments of symptoms and functioning. Because the capacity to learn from and adapt to adverse conditions are essential to the survival of any species, understanding the neurobiological pathways that mediate learning from traumatic experiences in an adaptive way is as important as understanding the etiology of PTSD and other trauma-related maladaptive consequences. Biological models that trace the causal cascade of post-traumatic events in the brain and neuroendocrine systems may offer a multiplicity of possibilities for intervention. It is well established that conditioned responses are robust and persistent. Moreover, the primary mechanism of habituation is overlearning rather than extinction. Interventions that promote overlearning may therefore prove to be the most powerful and efficient preventative treatments. The therapeutics literature supports this hypothesis, in that brief psychosocial interventions based on sophisticated cognitive-behavioral models have proven effective in reducing suffering, symptom severity, and chronicity in individuals presenting with acute PTSD symptoms [27-29]. No acutely administered pharmacologic treatment to date has been shown effective in accelerating the process of recovery or in preventing the development of chronic PTSD. However, pharmacologic interventions that would prevent sensitization of circuits related to context-dependent threat perception, dysregulation of affect, and/or dysregulation of normal circadian rhythms are of theoretical interest and deserve further study.