Many patients with hepatocellular carcinoma(HCC) are diagnosed in an advanced stage, so they cannot be offered the option of curative treatments. The results of systemic chemotherapy are unsatisfactory and this has led to molecular targeted approaches.HCC develops in chronically damaged tissue due to cirrhosis in most patients. Several different cell types and molecules constitute a unique microenvironment in the liver, which has significant implications in tumor development and invasion. This, together with genome instability, contributes to a significant heterogeneity which is further enhanced by the molecular differences of the underlying causes. New classifications based on genetic characteristics of the tissue microenvironment have been proposed and key carcinogenic signaling pathways have been described. Tumor and adjacent tissue profiling seem biologically promising, but have not yet been translated into clinical settings. The encouraging first results with molecular- genetic signatures should be validated and clinically applicable. A more personalized approach to modern management of HCC is urgently needed. Many of the patients with hepatocellular carcinoma (HCC) are diagnosed in an advanced stage, so they can not be offered the option of curative treatments. The results of the combination chemotherapy are unsatisfactory and this has led to molecular identification approaches. HCC develops in chronically damaged tissue due to Several different cell types and molecules constitute a unique microenvironment in the liver, which has significant implications in tumor development and invasion. This, together with genome instability, contributes to a significant heterogeneity which is further enhanced by the molecular differences of the underlying causes. New classifications based on genetic characteristics of the tissue microenvironment have been proposed and key carcinogenic signaling pathways have been described. Tumor and adjacent tissue profiling seem biologically promising, but have not yet been translated into clinical settings. The encouraging first results with molecular-genetic si gnatures should be validated and clinically applicable. A more personalized approach to modern management of HCC is urgently needed.