α1-Antitrypsin (α1AT) deficiency is one of the most common inherited disorders of metabolism in the United States and provides a striking example of the impact of an inherited disease on two different patient populations. In adults, progressive destructive lung disease presenting between 25–45 years of age is the most common clinical manifestation of this disorder. In children, α1AT deficiency most often presents as neonatal cholestasis, which progresses to cirrhosis usually before age 8. Although there is overlap in the clinical manifestations in both age groups, the bimodal age distribution remains a remarkable observation in the context that both clinical features result from the same gene mutations. While the α1AT gene is highly polymorphic and α1AT deficiency may result from several different mutations within the α1AT gene, the majority of α1AT-deficient individuals are protease inhibitor type Z. A single base transversion of guanine to adenine altering the amino acid composition of α1AT in a critical area of the molecule is responsible for the α1AT Z variant. The diagnosis of α1AT deficiency is confirmed by a reduced α1AT serum concentration, characteristic isoelectric focusing pattern of the enzyme, and a family study confirming the inheritance of the “deficiency” allele. New techniques for the identification of deficiency alleles include direct DNA sequencing, allele-specific amplification of known mutations utilizing specific oligonucleotides directed to the specific base alterations, and haplotype analysis of DNA restriction fragments. Therapy for the lung disease associated with α1AT deficiency is available in the form of α1AT derived from pooled human sera. Unfortunately, there are no current therapeutic alternatives to liver transplantation in patients with severe liver disease secondary to α1AT deficiency.