The past 50 years have seen huge advances in our understanding of the pathogenesis of alpha-1 antitrypsin deficiency. It is widely accepted that the common severe Z deficiency allele causes mutant alpha-1 antitrypsin to be retained as inclusions of ordered polymers within hepatocytes. This causes circulating deficiency of an important proteinase inhibitor, an excess of neutrophil elastase and therefore tissue destruction and emphysema. However, the past two decades have led to a shift in the paradigm from a disease that results from simply an imbalance of enzymes and inhibitors to one in which there is growing recognition that the polymers themselves play a role, not only in the liver disease, but also in the associated emphysema, vasculitis and panniculitis. Much of this has been dealt with in previous, more detailed reviews. I have therefore taken this opportunity of the 50th anniversary of the discovery of alpha-1 antitrypsin deficiency to present a personal overview of the past 22 years. This review considers the description of alpha-1 antitrypsin polymers, an assessment of their role in the different components of alpha-1 antitrypsin deficiency, the role of polymers in other diseases and how our understanding of polymerisation can be exploited to develop novel therapeutic strategies. The ultimate aim of our work is to develop a cure for alpha-1 antitrypsin deficiency.