Alpha-1-antitrypsin (a1AT) Deficiency is a metabolic genetic disease in which individuals homozygous for the mutant Z a1AT gene are at risk for liver and lung disease. Homozygotes, called PIZZ in World Health Organization nomenclature, occur in approximately 1 in 2000 births in North American and European populations. A1AT is a protein synthesized in large quantities by the liver, leukocytes, and other tissues and then secreted into serum and extracellular fluid. Its physiologic function is to inhibit neutrophil proteases during periods of inflammation in order to protect host tissues from non-specific inflammatory injury. The mutant Z gene of a1AT directs the synthesis of a mutant protein which folds abnormally in the endoplasmic reticulum of hepatocytes during biogenesis and is retained intracellularly rather than being efficiently secreted. This intracellular accumulation of a1AT mutant Z protein within hepatocytes can cause liver injury, cirrhosis and hepatocellular carcinoma, and the lack of circulating anti-protease activity leaves the lung vulnerable to injury and the development of emphysema. There is a high degree of variability in the clinical manifestations among PIZZ patients, suggesting a strong influence of genetic and environmental disease modifiers. Cigarette smoking has been identified as an especially strong risk factor for the development of PIZZ associated emphysema. The accumulation of the a1AT mutant Z protein within hepatocytes triggers an injury cascade which includes aspects of ER stress, caspase activation, and apoptosis which appears to lead to liver injury, fibrosis and cirrhosis. There is no specific treatment for PIZZ associated liver disease, other than standard liver disease supportive care and liver transplantation. Studies of the processes of intracellular injury, and of new therapies for this disease, are areas of intense and ongoing investigation.