It is well-known that 75% of risk factors of chronic liver disease (CLD) are related to nutrition. These circumstances potentially progress towards liver steatosis, fibrosis and hepatocellular carcinoma (HCC). It still represents an enormous problem for the economy of public health worldwide. Furthermore, validated prevention programs could be the solution. Recent knowledge in understanding molecular determinants of energy liver metabolism and new genetic markers offers new insights into the pathogenesis of CLD and HCC. The main rationale of the present issue is to provide a summary of recent insights into the inherited variants regulating lipid metabolism (steatohepatitis) and acquired mutation for early diagnosis of HCC, specifically focusing on the significance of antioxidant agents and genotyping tests as a cost-effectiveness tool for the prevention of liver disease. Several national healthy programs worldwide promote the daily use of antioxidant nutrients either for the prevention and/or as complementary and alternative medicines (CAM). This review could be advising for the planning of a large-scale clinical trial including a combination strategy of antioxidant agents and genotyping tests in patients with high risk of CLD.