Alpha (1)-antitrypsin deficiency is a common genetic disease in which individuals homozygous for the mutant Z allele are at risk for the development of liver disease and emphysema. The mutant Z protein product is synthesized in hepatocytes but then accumulates intracellularly rather then being appropriately secreted. The effects of the intracellular accumulation of the mutant Z protein in the liver include the formation of protein polymers, activation of autophagy, mitochondrial injury, and caspase activation, which progress in a cascade causing hepatocellular injury. Liver disease can occur at any age, although the majority of children are free of significant liver dysfunction. The variable clinical presentations suggest an important contribution of genetic and environmental disease modifiers. The heterozygous carrier state for the mutant Z gene, present in 1.5% to 3% of the population, is not itself a common cause of liver injury but may be a modifier gene for other liver diseases.