Obesity and type 2 diabetes continue to be major public health burdens with type 2 diabetes rising in epidemic proportions. Since known risk factors do not explain all of the variance in the population, it is important to identify novel risk factors that can lead to development of new preventive measures. Chronic psychological stress and depression are associated with type 2 diabetes but the mechanism remains unclear. Neuroendocrine changes induced by these stressors, specifically activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), might provide a unifying explanation. The objectives of this review are (1) to summarize the metabolic impact of HPA axis and SNS dysfunction induced by depression and stress, (2) to summarize the relation of neuroendocrine parameters to risk factors for diabetes, (3) to discuss the limitations of assessing neuroendocrine function in population-based and intervention studies, and (4) to summarize the evidence of the impact of stress reduction, by cognitive behavior therapy (CBT), on neuroendocrine factors and on outcomes in diabetes and obesity.