The UPR^ER 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 UPR^ER to coordinate physiological processes between cells and tissues. Recent evidence suggests that the activation of the UPR^ER can itself be communicated between cells. This cell non-autonomous route to UPR^ER 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 UPR^ER signaling a potential source of novel future therapeutics.