&agr;1-antitrypsin (&agr;1AT) deficiency is a common lethal hereditary disorder of white persons of European descent. The condition is characterized by reduced serum levels of &agr;1AT, a 52-kDa glycoprotein synthesized chiefly in the liver and, to a lesser extent, by macrophages and neutrophils. &agr;1AT acts as an antiprotease and is the physiological inhibitor of neutrophil serine proteases such as neutrophil elastase cathepsin G and proteinase 3. The clinical manifestations of &agr;1AT deficiency occur chiefly in the lung, with a high risk of emphysema occurring by the third or fourth decade of life. Cigarette smoking accelerates the development of emphysema in persons with &agr;1AT deficiency. There is also an increased risk of liver disease in &agr;1AT deficiency, which occurs mostly in childhood. In this review, we will define further the diagnosis of &agr;1AT deficiency and its clinical manifestations and describe the therapeutic strategies that are currently being developed to treat the hepatic and pulmonary disease associated with this condition.