Primary liver cancer is the fifth most common cancer worldwide and hepatocellular carcinoma (HCC) accounts for over 85% of all primary liver cancers. The clinical management of advanced and metastatic HCC is challenging on many counts. Besides largely occurs within a background of underlying chronic liver disease and cirrhosis, HCC is a phenotypically and genetically heterogeneous polyclonal disease and resistant to most conventional chemotherapy. Early manifestation of HCC is characteristically slow growing with few symptoms, and HCC is therefore often diagnosed at an advanced stage when potentially curative surgical or local ablative therapy is not feasible. In this review, I have summarized my presentation at the recent HCC workshop at IARC, Lyon, on our knowledge generated from comprehensive molecular studies of primary liver cancer tissues and attempt to translate these results to gain molecular insights, especially on identification of biomarkers that could confer pathological and functional changes associated with the pathogenesis and progression of HCC, hoping to provide important molecular basis for the development of novel diagnosis and treatments to alter clinical outcomes of this disease.