Hepatocellular carcinoma is known to be a common primary liver malignancy and a serious leading cause of cancer-related mortality globally. Hence, ongoing recent advances in the genetic field regarding hepatocellular carcinoma paid researchers great attention to identifying various biomarkers to act as diagnostic and prognostic tools for the early detection of hepatocellular carcinoma and also developing targeted therapeutic agents that are indicated and available for advanced stages of hepatocellular carcinomas, however, their antitumor efficacy remains limited and under investigations. Therefore, our review summarized the genetic studies of liver cancer focusing on the somatic mutations, copy number variations, and epigenetic modifications that represent early alterations and oncodrivers in hepatocarcinogenesis, Moreover, the identification of genetic signatures and proteomic targets through hepatocellular carcinoma-related genome-wide screening, to show the ongoing clinical application of such analysis to facilitate diagnosis, prognosis and management of patients with hepatocellular carcinoma for a better outcome.