Individuals exposed to traumatic events might develop a condition known as posttraumatic stress disorder (PTSD). PTSD affects memory and sleep, has long-lasting effect on hypothalamic-pituitary-adrenal (HPA)-axis, and has an impact on social and occupational functioning. Although, the original conceptualization in models of stress sensitization, fear conditioning and failure of extinction, has led to empirical data in support of the psychobiological notions, there is still no cure for PTSD. To achieve this, we need to have more insight in the relation between the biological alterations and the psychopathology of PTSD. But valid biomarkers for PTSD, linked to the underlying mechanism, are not available. These biological biomarkers are needed to facilitate the research towards the understanding of the underlying mechanism and the development of efficacious medicines to treat PTSD. Still then, retrospective studies in humans are difficult to perform and most studies fail to control for the effect of trauma itself, limiting the results of the studies. Therefore, a firm basis is needed on controlled animal research that optimally uses cross-species characteristics by integration of the mechanistic disturbance with symptoms, which can be applied to animals and humans alike. Knowledge achieved from translational research, using markers with an open eye towards human validity, will finally lead to novel therapeutic approaches.