The aging process is characterized by tissue decline and the onset of age-associated disease. It is not, however, immutable, and aging can be modulated by various genetic and environmental means. One of the interventions that can modulate lifespan is the activation of cellular stress responses, including the unfolded protein response in the endoplasmic reticulum (UPRER). The ability to activate the UPRER declines with age, while its constitutive activation can extend longevity. It also plays complex roles in the onset and progression of many age-related diseases. Understanding how the UPRER changes with age, and how this impacts upon disease development, may open new therapeutic avenues for the treatment of a range of age-associated diseases.