The UPRER is an important regulator of secretory pathway homeostasis, and plays roles in many physiological processes. Its broad range of targets and ability to modulate secretion and membrane trafficking make it perfectly positioned to influence intercellular communication, enabling the UPRER to coordinate physiological processes between cells and tissues. Recent evidence suggests that the activation of the UPRER can itself be communicated between cells. This cell non-autonomous route to UPRER activation occurs in multiple species, and enables organism-wide responses to stress that involve processes as diverse as immunity, metabolism, aging and reproduction. It may also play roles in disease progression, making the pathways that mediate cell non-autonomous UPRER signaling a potential source of novel future therapeutics.