Chronic liver disease and primary liver cancer are a massive global problem, with a future increase in incidences predicted. The most prevalent form of primary liver cancer, Hepatocellular carcinoma (HCC), occurs after years of chronic liver disease. Mutations in the genome are a causative and defining feature of all cancers. Chronic liver disease, mostly at the cirrhotic stage, causes the accumulation of progressive mutations which can drive cancer development. Within the liver a Darwinian process selects out dominant clones with selected driver mutations but also leaves a trail of passenger mutations which can be followed allowing tracking of this evolution. Understanding what causes specific mutations and how they combine with one another to form cancer is a question at the heart of understanding, preventing and tackling liver cancer. Here we review the landscape of gene mutations in cirrhosis, especially those paving the path toward HCC development characterised by recent studies capitalising on technological advances in genomic sequencing. With these insights we are beginning to understand how cancers form in the liver, particularly on the background of chronic liver disease. This knowledge may soon lead to breakthroughs in the way we detect, diagnose and treat this devastating disease.