Abstract:  Stress, such as nutrient deprivation, viral infections, inflammation, heat shock, or lipid accumulation, imposes a serious threat to the body. These stimuli, acting both on the central control stations of the stress system and its final effectors, catecholamines and glucocorticoids, and on the peripheral target tissues, can modulate insulin action in the body. Metabolic complications, such as diabetes, visceral obesity, and atherosclerosis have emerged as major health threats in the modern societies. Indeed, obesity and atherosclerosis are regarded as states of chronic low‐grade inflammation, while inflammatory mediators and lipid accumulation can evoke a chronic stress at the cellular level, principally affecting the endoplasmic reticulum (ER). It has recently been shown that ER responds to metabolic stressors through a well coordinated molecular response that involves the transcriptional activation of multiple genes, the attenuation of protein synthesis and degradation of the ER‐localized misfolded proteins, and the onset of apoptosis. This article examines the emerging role of stress on ER and its possible link with obesity, insulin resistance, and type 2 diabetes.