Cirrhosis is a premalignant condition leading to hepatocellular carcinoma. Cirrhotic nodules are surrounded by a rim of CK 7/CK19-positive biliary cells termed ductular reaction. Half of all regenerative cirrhotic nodules are thought to be monoclonal by studying the pattern of inactivation of the X-linked human androgen receptor gene (HUMARA). Using a new technique for lineage tracing in human liver based on the identification in the mitochondrial DNA of mutations in the cytochrome c oxidase (CCO) gene, the authors discovered that 20% of regenerative nodules were monoclonal; in addition they showed that hepatic progenitor cells within abutting CCO-deficient cells of the ductular reaction had the same mutations as the adjacent regenerative nodule, indicating a common cell origin. It is the first direct evidence that regenerative nodules in cirrhosis can be derived from hepatic progenitor cells.