Alpha₁-antitrypsin (α₁-AT) is the most abundant circulating inhibitor of serine proteases and therefore is essential to normal protease–anti-protease homeostasis. Inheritance of two parental α₁-AT deficiency alleles is associated with a substantially increased risk for development of emphysema and liver disease. In very rare circumstances individuals may inherit α₁-AT null alleles. Nullα₁ -AT alleles are characterized by the total absence of serum α₁-AT. These alleles represent the extreme end in a continuum of alleles associated with α₁-AT deficiency. The molecular mechanisms responsible for absence of serum α₁-AT include splicing abnormalities, deletion ofα₁ -AT coding exons and premature stop codons. While these alleles comprise only a small proportion ofα₁ -AT alleles associated with profound α₁-AT deficiency, studies of their molecular mechanisms provide valuable insights into the structure, gene expression and intracellular transport ofα₁ -AT.