Extremely deficient levels of alpha-1-antitrypsin (ALPHA1AT) predispose such deficient individuals to the development of emphysema and cirrhosis. Protease inhibitor (Pi) typing has clarified that the inherited deficiency is codominant. A glycoprotein with antigenic characteristics of alpha1AT is found in the endoplasmic reticulum of the hepatocytes of individuals with PiZ phenotype. No therapy is available except liver transplantation. Although biochemical advances in defining the nature of alpha1AT deficiency are progressing, the pathogenesis of the liver disease remains an enigma.