Alpha-1 antitrypsin deficiency (A1ATD) is a hereditary disease caused by autosomal codominant mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (A1AT) protein, leading to mutant A1AT protein retention in the endoplasmic reticulum of hepatocytes and decreased circulating functional A1AT protein. Patients with A1ATD can present with variable symptoms and signs resulting from liver injury, skin damage, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, panniculitis, bronchiectasis, and pulmonary dysfunction. They also have an increased risk of lung cancer and hepatocellular carcinoma. The most common pathogenic alleles of A1ATD are the Z (Glu342Lys) and the S (Glu264Val) variants. The homozygous Pi∗Z mutation (Pi∗ZZ genotype) causes the most severe A1ATD disease in both pediatric and adult patients. Histologic examination of the liver in patients, especially those with the Pi∗ZZ genotype, commonly shows intracytoplasmic eosinophilic protein aggregates (A1AT globules). Definite diagnosis of A1ATD relies on serum A1AT protein phenotype analysis or SERPINA1 genotyping in the suspected individuals. Genetic and environmental modifiers both play important roles in disease development and progression.