In this “see-saw” depiction of health and homeostasis versus chronic disease and pathology, data support that in health and homeostasis, low levels of RAGE ligands, likely both due to low level of production and/or effective mechanisms of clearance, are present in the circulation and in the tissues. In response to acute stress, rapid homeostatic responses to cellular stress and rapid resolution occur. However, on the other side of the balance, in chronic disease and pathological settings, such as obesity, diabetes, Alzheimer’s disease, and chronic inflammation, as examples, higher levels of RAGE ligands pervade the circulation and tissue, accounted for by accelerated production and/or reduced clearance. In such settings, compounded by oxidative and inflammatory stresses, we predict that the RAGE ligands contribute to prolonged responses to stress and, ultimately, to delayed resolution – all processes that mediate tissue damage.