Stressful stimuli in healthy subjects trigger activation of a consistent and reproducible set of brain regions; yet, the notion that there is a single and constant stress neuromatrix is not sustainable. Indeed, after chronic stress exposure there is activation of many brain regions outside that network. This suggests that there is a distinction between the acute and the chronic stress neuromatrix. Herein, a new working model is proposed to understand the shift between these networks. The understanding of the factors that modulate these networks and their interplay will allow for a more comprehensive and holistic perspective of how the brain shifts 'back and forth' from a healthy to a stressed pattern and, ultimately, how the latter can be a trigger for several neurological and psychiatric conditions.