The endoplasmic reticulum (ER) is the first sub-cellular compartment encountered by secretory proteins en route to the plasma membrane. Newly synthesized secretory proteins translocate into the ER lumen and acquire their correct conformation prior to being exported to later compartments. When folding is not properly achieved, proteins accumulate in the ER due to resident quality control machineries and terminally misfolded proteins are ultimately degraded through the ER-associated degradation pathway. All these molecular machines function in a coordinated fashion to restore and maintain ER homeostasis. A fifth molecular machine plays a coordinating role in the ER. Indeed, the ER stress signaling machinery signals ER dysfunction to the rest of the cell and consequently integrates the functions of the four other molecular machines to improve their operation in stressful conditions. In this work, we have attempted to define the ER as a molecular biological system regulated by its own specific signaling pathways defined as the Unfolded Protein Response to delineate a systems biology approach of ER stress signaling.