Chronic psychological stress exerts a clinically significant influence metabolically, resulting in chronic disease through sustained activation of neuroendocrine and inflammatory pathways. Although acute stress responses are adaptive, persistent activation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system results in cortisol dysregulation, chronic inflammation and further disease due to maladaptive behavioral responses. These issues directly contribute to the development of type 2 diabetes mellitus, obesity, and hypertension. Recent evidence supports cortisol not only as a mediator, but also as a biomarker for stress related disease, with effects on insulin resistance, visceral adiposity, and increased blood pressure. Furthermore, stress related eating behaviors as well as racial and ethnic disparities may amplify these physiological mechanisms, increasing disease risk in these populations. Understanding chronic stress as a direct, controllable aspect in chronic disease is essential in the treatment and mitigation of type 2 diabetes mellitus, obesity, and hypertension.