The marked disruption of the homeostasis of a physiological system, be it a cell, tissue, organ, or whole organism, is more commonly known as stress. In many ways, aging can be considered the ultimate stress. However, physiological systems are constantly exposed to more acute stresses. Advances in our understanding of the molecular response of several physiological systems to both physiologic and pathologic stress is discussed in this Review Series. It is hoped that such understanding will facilitate the development of approaches to ameliorate some of the limitations these stresses place on individuals. However, as pointed out in many of the articles, much remains to be learned before such approaches can be envisioned.