There is increasing interest in the role of misfolded proteins in disease. Protein misfolding is widely recognized to be associated with diseases as diverse as Alzheimer’s, Huntington’s, and Parkinson’s, the amyloidoses and prion encephalopathies. Protein misfolding also plays a role in two important obstructive lung diseases: cystic fibrosis and a1-antitrypsin deficiency. The aim of this conference was to review the basic mechanisms of endoplasmic reticulum (ER) stress and ER-associated degradation and assess how these mechanisms apply to cystic fibrosis and a1-antitrypsin deficiency. This is particularly exciting because small molecules have been developed that improve the folding and activation of mutant cystic fibrosis transmembrane regulator protein (the protein that is defective in cystic fibrosis). Moreover, there is increasing interest in developing chaperones that can increase the folding and secretion of a1-antitrypsin. This strategy is complimented by a second approach to specifically target the protein–protein interaction that underlies the retention of mutant a1-antitrypsin within the liver. The conference started with an introductory lecture by Gerry McElvaney (Dublin, Ireland). Gerry explained how mutants of a1-antitrypsin and a1-antichymotrypsin form ordered polymers that are retained within the endoplasmic reticulum of hepatocytes. He showed that the accumulation of intracellular a1-antitrypsin could activate the ER stress response and apoptosis. Gerry expanded our understanding of this process by examining the effect of the expression of mutant protein in monocytes and a range of cell cultures. He reported that the expression of mutant Z a1-antitrypsin leads to the activation of NF-kB and the release of inflammatory cytokines such as IL-6 and IL-8. Polymers of mutant a1-antitrypsin can also form locally in the extracellular space of the lungs. These polymers are chemotactic for human neutrophils. Thus, the lung disease associated with a1-antitrypsin deficiency is likely to be a combination of insufficient a1-antitrypsin within the lung to inhibit proteolytic enzymes such as neutrophil elastase, the proinflammatory effects of extracellular polymers, and the intracellular ER stress releasing inflammatory cytokines. Gerry argued that this may be relevant to ‘‘usual COPD’’ that develops in smokers with normal levels of a1-antitrypsin. Cigarette smoke can also cause ER stress, the unfolded-protein response, and apoptosis. Thus ER stress associated with a1-antitrypsin deficiency may provide a model for smoke-related ER stress associated with ‘‘usual COPD.’’