Stress can be defined as a state of threatened homeostasis or disharmony. An intricate repertoire of physiologic and behavioral responses is mobilized under stressful situations forming the adaptive stress response that aims to reestablish the challenged body equilibrium. The hypothalamic-pituitary-adrenal axis and the central and peripheral components of the autonomic nervous system constitute the two main pillars that subserve the vital functions of the stress system. Chronic stress represents a prolonged threat to homeostasis that can progressively lead to a deleterious overload with various complications caused by both the persistent stressor and the detrimental prolongation of the adaptive response. Recent data indicate that chronic stress is associated to derangement of metabolic homeostasis that contributes to the clinical presentation of visceral obesity, type 2 diabetes, atherosclerosis and metabolic syndrome. Notably, indices of stress in the modern western societies correlate with the increasing incidence of both obesity and the metabolic syndrome which have reached epidemic proportions over the past decades. The pathogenetic mechanisms that accommodate these correlations implicate primarily the chronic hyperactivation of the HPA axis under prolonged stress, which favors accumulation of visceral fat, and vice versa; obesity constitutes a chronic stressful state that may cause HPA axis dysfunction. In addition, obesity is being now recognized as a systemic low grade inflammatory state that contributes to the derangement of the metabolic equilibrium, implicating the adipocyte secretion of adipokines to the pathogenesis of several components of the metabolic syndrome. Understanding the mechanisms that mediate the documented reciprocal relationships between stress and metabolic homeostasis will hopefully provide novel insights to the pathophysiology of obesity, type 2 diabetes, and their cardiometabolic complications, and will help the quest for more specific and effective therapeutic interventions.