The unfolded protein response (UPR) is a complex adaptive stress response of the endoplasmic reticulum (ER) that maintains ER function for cell survival. The UPR is typically activated by the accumulation of aberrant proteins within the ER lumen, but also by aberrant lipid mixtures. Excessive accumulation of lipids causes metabolic abnormalities and cells death including loss of pancreatic insulin-producing beta cells. Recently, we identified a broad range of cellular defects that induce ER stress, presumably via aberrant lipids at the ER. From these observations, we hypothesize that communication between the ER and other cellular compartments is critical to maintain ER membrane integrity and to prevent unresolved ER stress associated with metabolic diseases. I will discuss our latest findings on the role of the UPR in different model organisms and model systems.