An initial precipitating injury (i.e. the first seizure, brain trauma, hypoxia/ischemia) compromises the structural integrity of limbic circuits leading to neuronal rearrangements and cell loss in stress-regulatory regions such as the hippocampus, prefrontal cortex, and amygdala. These changes give rise to epileptogenesis and the subsequent development of TLE, while simultaneously compromising the functional integrity of stress regulatory mechanisms resulting in HPA axis hyperactivity and increased vulnerability for the development of psychopathologies (depression and anxiety). Both epileptic seizures and chronic exposure to excess glucocorticoids may potentiate the neuronal damage on limbic stress-regulatory regions. Furthermore, HPA axis hyperactivity results in exaggerated responses to stress that may facilitate epileptic discharges.