Background: The European Respiratory Society recently published an important statement reviewing available evidence on diagnosis and treatment of lung disease associated to alpha-1 antitrypsin deficiency (AATD). Several issues on this topic still remain unresolved and subject of interpretation according to different standard procedures and healthcare systems worldwide. The purpose of this commentary is to offer a critical contribution to most of these controversial issues in light of an Italian perspective for the management of this disease. Main body: The clinical spectrum of AATD lung disease might include different manifestations and the traditional paradigm of a younger emphysematous patient has been revealing insufficient. Targeting with appropriate testing only COPD patients might be considered a limited approach leading to underestimation of the real prevalence of the disease. Several reports have suggested the association between AATD and other chronic respiratory conditions, as asthma and bronchiectasis. A deeper evaluation of clinical, radiological, microbiological and functional variables is, therefore, needed in order to investigate different phenotypes in AATD patients. In addition, a new line of translational research in AATD might focus on the development of personalized therapeutic regimens taking into account the patient clinical profile and needs. Conclusions: Over the past years, AATD has been interpreted as a common mechanism of inflammatory disequilibrium and tissue damage across different conditions. Future research is gradually pointing toward this new paradigm by expanding the evidence of the role of AAT as a potent immunomodulatory and anti-inflammatory drug in conditions different from pulmonary emphysema.