The respiratory tract has a surface area of approximately 70 m(2) that is in direct contact with the external environment. Approximately 12,000 l of air are inhaled daily, exposing the airway epithelium to up to 25 million particles an hour. Several inhaled environmental triggers, like cigarette smoke, diesel exhaust, or allergens, are known inducers of endoplasmatic reticulum (ER) stress and cause a dysregulation in ER homeostasis. Furthermore, some epithelial cell types along the respiratory tract have a secretory function, producing large amounts of mucus or pulmonary surfactant, as well as innate host defense molecules like defensins. To keep up with their secretory demands, these cells must rely on the appropriate functioning and folding capacity of the ER, and they are particularly more vulnerable to conditions of unresolved ER stress. In the lung interstitium, triggering of ER stress pathways has a major impact on the functioning of vascular smooth muscle cells and fibroblasts, causing aberrant dedifferentiation and proliferation. Given the large amounts of foreign material inhaled, the lung is densely populated by various types of immune cells specialized in engulfing and killing pathogens and in secreting cytokines/chemokines for efficient microbial clearance. Unfolded protein response signaling cascades have been shown to intersect with the functioning of immune cells at all levels. The current review aims to highlight the role of ER stress in health and disease in the lung, focusing on its impact on different structural and inflammatory cell types.