Background: Hepatocellular carcinoma (HCC) poses a major challenge because of the extreme variability of the clinical outcome, which makes it difficult to properly stage the disease and thereby estimate the prognosis. There is growing evidence that this heterogeneous clinical behavior is attributable to several different biological pathways. A novel approach to mapping these differences is by investigating the epigenetics associated with certain clinical aspects.Design: Herein, the relevance of these molecular differences in combination with the biological and molecular pathways regulating the clinical outcome will be discussed. Use of a mechanistic and pathogenic approach to clarify the natural history of HCC is not just an academic speculation but should help to develop new therapies and to tailor these therapies to each individual patient.Conclusion: New biological therapies targeting components of the tumoral or peritumoral microenvironment are crucial to the fight against HCC. However, biological redundancies and the presence of several growth factors, hormones, cytokines, etc., potentially involved in HCC tumor progression make it difficult to assess the best target. Sorafenib, a multi-tyrosine kinase inhibitor, blocks the functions of different growth factors present in the tissue microenvironment. The use of Sorafenib in patients with HCC offers a new approach to the therapy of this disease, stimulating research focusing on the development of drugs based on new molecular and pathogenic insights.