While working in previous laboratories, we were involved in the development of a molecular classification of hepatocellular carcinoma (HCC), and an integrated model of HCC prognosis by combining clinical, pathological and genomic data. As a follow-up, we evaluated the role of DNA methylation profiles as potential prognostic biomarkers. We also found de-regulation of MTOR and NOTCH signaling pathways in a subset of HCCs, and show how their selective blockage in experimental models induced significant tumor responses. The long-term goal of our lab is to redefine the current model for HCC decision-making, which now relies only on clinical variables. We expect to provide the proof-of-principle to incorporate powerful readouts of tumor biology in HCC risk stratification, and identify key events in tumor progression and mechanisms of drug resistance.