Stress can be defined as a state of threatened body homeostasis which mobilizes a spectrum of adaptive physiologic and behavioral responses via the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), i.e., the two main effector pathways of the stress system. These adaptive responses aim to reestablish the challenged body equilibrium (allostasis/cacostasis) and are programmed to promptly subside once this has been achieved. Growing evidence suggests that chronic stress significantly affects glucose homeostasis and is implicated in the dysregulation of metabolism over time. Indeed, various stress indices have been shown to exhibit a positive correlation with the increasing prevalence rates of both obesity and type 2 diabetes, particularly in Western societies. Recent data further indicate that chronic stress, associated with hypercortisolemia and prolonged SNS activation, promotes visceral accumulation of adipose tissue and insulin resistance, hence, contributing to the clinical presentation of central obesity, type 2 diabetes, and cardiovascular disease. On the other hand, obesity induces a systemic low-grade inflammation, mediated by proinflammatory adipokines which activate the acute phase reaction and act as an additional chronic stimulus to the stress system activation. Accordingly, a vicious cycle is formed, whereby chronic activation of the stress system contributes to obesity-related inflammation and insulin resistance, and vice versa.