SERPINA1, α-antitrypsin (AAT) is an acute phase protein, a member of the serpin (serine protease inhibitor) super family and one of the most abundant protease inhibitors in the circulation. The clinical importance of AAT is emphasized in persons with inherited AAT deficiency who exhibit high risk of developing early onset pulmonary emphysema, neonatal hepatitis, liver cirrhosis, which may appear at any age, and in rare cases panniculitis and vasculitis. The most common and severe AAT deficiency is associated with the Z (Glu342 to Lys) mutation. It is also well established that Z AAT deficiency results from the polymerization and accumulation of the misfolded AAT protein. Consequently, low levels of circulating Z AAT are assumed to be inadequate to neutralize elastolytic activity and to prevent lung tissue damage. Novel studies, however, are expanding the link between AAT and human diseases. Associations are shown between reduced AAT levels and HIV type 1 infection, hepatitis C infection, diabetes mellitus, vasculitis, panniculitis and other diseases. Given the importance of the protease/antiprotease imbalance in causing emphysema, augmentation of circulating AAT is used as a specific therapy for patients with AAT deficiency-related emphysema but not for those with liver diseases. According to the novel findings, therapy with AAT possesses antiinflammatory and immuno-modulatory effects across a broad spectrum of experimental models of systemic and local inflammation. Hence, in this article we will discuss putative new directions for the clinical use of therapy with AAT.