The hyperactivity of the HPA axis due to long-term stress results in an abnormally high level of glucocorticoids. A limbic system structure, the hippocampus has the highest number of receptor sites for glucocorticoids. Thus, making it highly vulnerable to damage during elevated levels of glucocorticoids, through neurotoxicity and metabolic challenges. In addition, this paper largely focuses on the effects of stress on the hippocampus, e.g., changes in hippocampal volume, as a contributing factor in the psychophysiology of a myriad of mental health problems. Most disorders follow the diathesis-stress trajectory where the symptoms begin to precipitate once a major stressor is experienced with or without a predisposition and the effects of chronic stress, in particular, perpetuate the symptoms. Indeed, stress plays a significant role in mental health and is hard to dodge. Nevertheless, to nurture our mental health well-being we should try to minimize stress the best we can.