The endoplasmic reticulum (ER) is a metabolic organelle and an ideal nutrient sensor. In response to hypoglycemia, hyperglycemia or fatty acid overload, the ER triggers the unfolded protein response, which represses protein synthesis, alters insulin responsiveness and favors apoptosis. In addition, the ER affects steroid hormone activation and autophagy. The primary aim of these responses is to adjust the metabolism to environmental changes. Failure of the ER to adapt to changes in nutrient availability can result in a pathological transition in ER functions, as observed in cases of obesity-related diseases. This review highlights the recent evidence that the ER has a prominent role in cellular adaptation, as well as in the pathomechanism of type 2 diabetes.