Hepatocellular carcinoma (HCC) is a leading cause of cancer related mortality in the world and it has limited treatment options. Understanding the molecular drivers of HCC is important to develop novel biomarkers and therapeutics.HCC arises in a complex background of chronic hepatitis, fibrosis and liver regeneration which lead to genomic changes. Here, we summarize studies that have expanded our understanding of the molecular landscape of HCC.Recent technological advances in next generation sequencing (NGS) have elucidated specific genetic and molecular programs involved in hepatocarcinogenesis. We summarize the major somatic mutations and epigenetic changes have been identified in NGS-based studies. We also describe promising molecular therapies and immunotherapies which target specific genetic and epigenetic molecular events.The genomic landscape of HCC is incredibly complex and heterogeneous. Promising new developments are helping us decipher the molecular drivers of HCC and leading to new therapies.