α₁-Antitrypsin deficiency (AATD) is an inherited metabolic disorder in which mutations in the coding sequence of theSERPINA1gene prevent secretion of α₁-antitrypsin (α₁-AT) and cause predisposition to pulmonary and liver diseases. The heterogeneity of clinical manifestations in AATD is related to the complexity of biological function of α₁-AT. The role of smoking is crucial in the natural history of lung damage progression in severe AATD individuals, even if it also partly explains the heterogeneity in lung disease. Lung damage progression in AATD can also be related to body mass index, exacerbation rate, sex, environmental exposure and specific mutations ofSERPINA1. Recent randomised controlled trials, together with previous observational work, have provided compelling evidence for the importance of early detection and intervention in order to enable patients to receive appropriate treatment and preserve functional lung tissue.