Alpha-1 antitrypsin Deficiency (AATD) is a common, but under recognized metabolic genetic disease. Although many mutations in the alpha-1 antitrypsin (AAT) gene are described, the Z variant is the allele overwhelmingly associated with liver disease. PI*ZZ homozygotes occur in approximately 1 in 2,000-5,000 births in North American and European populations. The AAT protein is synthesized in large quantities by the liver, and then secreted into serum. Its physiologic function is to inhibit neutrophil proteases in order to protect host tissues from non-specific injury during periods of inflammation. The mutant Z gene of AAT directs the synthesis of a mutant protein which folds abnormally during biogenesis in the endoplasmic reticulum of hepatocytes and is retained intracellularly, rather than efficiently secreted. Intracellular proteolysis pathways, including the proteasome and autophagy, are activated as a response to the intracellular burden of misfolded protein. The lack of circulating anti-protease activity leaves the lung vulnerable to injury and the development of emphysema. The intracellular accumulation of AAT mutant Z protein within hepatocytes can cause liver injury, cirrhosis and hepatocellular carcinoma by triggering a cascade of chronic hepatocellular apoptosis, regeneration, and end organ injury. There is no specific treatment for PI*ZZ associated liver disease, other than standard liver supportive care and liver transplantation. There is a high degree of variability in the clinical manifestations among PI*ZZ homozygous patients, suggesting a strong influence of as yet poorly characterized, genetic and environmental disease modifiers. Studies of the processes of intracellular injury have led to a new era of rational therapeutic development.